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5 pages, 195 KiB

Open AccessEditorial

Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?

by Constantin N. Baxevanis

Cancers 2023, 15(3), 881; https://doi.org/10.3390/cancers15030881 - 31 Jan 2023

Cited by 9 | Viewed by 1917

Abstract

Immune checkpoint inhibitors (ICIs) are in the spotlight of cancer treatment by increasing the probability for long-term survival in patients with metastatic disease and by considerably prolonging progression-free survival in patients at early disease stages [...] Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

Research

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19 pages, 3477 KiB

Open AccessFeature PaperArticle

Co-Targeting Luminal B Breast Cancer with S-Adenosylmethionine and Immune Checkpoint Inhibitor Reduces Primary Tumor Growth and Progression, and Metastasis to Lungs and Bone

by Ali Mehdi, Mikhael Attias, Ani Arakelian, Ciriaco A. Piccirillo, Moshe Szyf and Shafaat A. Rabbani

Cancers 2023, 15(1), 48; https://doi.org/10.3390/cancers15010048 - 22 Dec 2022

Cited by 6 | Viewed by 3370

Abstract

Breast cancer (BCa) is the most prevalent cancer in females and has a high rate of mortality, especially due to increased metastasis to skeletal and non-skeletal sites. Despite the marked clinical accomplishment of immune checkpoint inhibitor (CPI) therapy in patients with several cancers, [...] Read more.

Breast cancer (BCa) is the most prevalent cancer in females and has a high rate of mortality, especially due to increased metastasis to skeletal and non-skeletal sites. Despite the marked clinical accomplishment of immune checkpoint inhibitor (CPI) therapy in patients with several cancers, it has had limited success in luminal subtypes of BCa. Accordingly, recent efforts have focused on combination therapy with CPI, including epigenetic modulators, to increase response rates of CPI in luminal BCa. We have previously shown that S-adenosylmethionine (SAM), the ubiquitous methyl donor, has strong anti-cancer effects in various cancers, including all subtypes of BCa. In the current study, we took a novel approach and examined the effect of CPI alone and in combination with SAM on tumor growth and metastasis in a syngeneic mouse model of luminal B BCa. We showed that SAM decreases cell proliferation, colony-formation (survival), and invasion of luminal B BCa cell lines (Eo771, R221A) in vitro. In in vivo studies, in Eo771 tumor-bearing mice, either SAM or anti-PD-1 antibody treatment alone significantly reduced tumor growth and progression, while the SAM+anti-PD-1 combination treatment had the highest anti-cancer efficacy of all groups. The SAM+anti-PD-1 combination reduced the percentage of animals with lung metastasis, as well as total metastatic lesion area, compared to control. Additionally, the SAM+anti-PD-1 combination significantly reduced the skeletal lesion area and protected tibial integrity to a greater extent than the monotherapies in an Eo771 bone metastasis model. Transcriptome analysis of Eo771 primary tumors revealed significant downregulation of pro-metastatic genes, including Matrix metalloproteinases (MMPs) and related pathways. On the other hand, CD8⁺ T cell infiltration, CD8⁺ T cell cytotoxicity (elevated granzymes), and immunostimulatory genes and pathways were significantly upregulated by the combination treatment. The results presented point to a combination of SAM with CPI as a possible treatment for luminal B BCa that should be tested in clinical studies. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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Figure 1

Figure 1
Effect of SAM on proliferation, colony-formation (survival), and invasion of luminal B BCa cell lines. (A) Percentage proliferation (± SEM) relative to control at 1, 2, and 3 days after SAM treatment. Briefly, Eo771 (4 × 104) and R221A (1 × 104) cells were seeded in 6-well plates, treatment with SAM (200 μM) started 2 days after seeding, and they were treated every day for 3 days. Cells were trypsinized and counted 1, 2, and 3 days after SAM treatment. (B) Percentage survival fraction (± SEM) relative to control obtained from soft agar colony formation assay. The colony formation assay was performed after the regular proliferation assay, and then the treated Eo771 (5 × 103) and R221A (5 × 103) cells were plated. Media was replenished every 4–5 days and colonies were counted after 3 weeks. (C) Invasion assay was performed after performing the regular proliferation assay and then incubating the treated cells (1.25 × 105) for 18 h in two-compartment Boyden chambers coated with Matrigel. Top: Percentage invasion (± SEM) relative to control. Bottom: Representative images (lens, 40×; magnification, 400×) of invaded cells. Results are the mean of at least three independent experiments. Statistical significance was determined by (A) two-way ANOVA and (B, C) T-test in GraphPad prism. Significance values are represented by asterisks (*** p < 0.001; **** p < 0.0001). Full article ">Figure 2
PD-L1 expression and effect of PD-L1 intracellular signaling on cell proliferation of murine BCa cells. (A) Expression of PD-L1 in murine BCa cell lines analyzed by RT-qPCR. The fold change was relative to the expression of R221A. (B–D) Effect of SAM and anti-PD-L1 antibody on proliferation of murine BCa cells. (B) Eo771 (4 × 104), (C) R221A (1 × 104), and (D) EMT6 (4 × 104) cells were seeded in 6-well plates and were added to rPD-1 (0.2 μg/mL, day 3). The cells were treated with either control (only rPD-1), SAM (200 μM, day 2, 3, 4), anti-PD-L1 antibody (50 μg/mL, day 4), or SAM and anti-PD-L1 in combination. The results are the mean of at least three independent experiments. Proliferation is represented as the percentage proportional to the control (± SEM). Statistical significance was determined by one-way ANOVA in GraphPad prism. Significance values are represented by asterisks (ns; not significant; *** p < 0.001; **** p < 0.0001). Full article ">Figure 3
SAM, anti-PD-1 antibody, and the combination treatment decreased primary tumor growth in Eo771 tumor-bearing mice. (A) Eo771 (2 × 105 cells) were injected at the 4th m.f.p in B6 mice to induce tumor formation. The animals were treated with either the control (isotype matched IgG and PBS), SAM (80 mg/kg/day), anti-PD-1 antibody (5 mg/kg, twice per week), or combination. Tumor volumes were assessed at day 8, 15, and 20, and the animals were sacrificed at day 20. Results are presented as the mean ± SEM of tumor volume (n ≥ 7/group). (B) Percentage tumor growth inhibition (TGI) was calculated from tumor volumes at day 15 to day 20, relative to the control. (C) Tumor weight (mg ± SEM) was measured after tumor harvest on day 20. (D) Body weight (g ± SEM) of the mice was measured once a week. Statistical significance was determined by (A, D) two-way ANOVA; (B, C) one-way ANOVA in GraphPad prism. Significance values are represented by asterisks (ns, not significant; * p < 0.05; ** p < 0.01; *** p < 0.001 and **** p < 0.0001). Full article ">Figure 4
SAM, anti-PD-1 antibody, and the combination treatment decreased lung metastasis in Eo771 tumor-bearing mice. Briefly, mice were injected with Eo771 cells orthotopically at the m.f.p and treated with the four treatments indicated. At the end of the study, lungs of the mice were harvested, fixed using formalin, embedded in paraffin, sliced, and stained with H&E. (A) Representative histology images of mouse lung showing the whole lung and magnified images to show metastatic lesions from each group except the SAM+anti-PD-1 antibody combination group, which had no lesions in this sample. Lens: top; 4×; bottom; 20×. Magnification: top; 40×; bottom; 200×. (B) Total metastatic lesion area (µm2 ± SEM) for each group (n = 4/group). Total metastatic lesion area was calculated by annotating all the metastatic lesions in the entire lung of a mouse using the ImageScope annotation tool, which gives the selected area. Then, all the lesion areas were added together. (C) Percentage of mice with lung metastasis in each group. Statistical significance was determined by (B) one-way ANOVA in GraphPad prism. Significance values are represented by asterisks (* p < 0.05; ** p < 0.01). Full article ">Figure 5
The SAM and anti-PD-1 antibody combination decreases bone metastasis and protects the bone from damage caused by aggressively growing tumor lesions. Briefly, mice were injected with Eo771 cells intra-tibially and treated with either control (isotype matched IgG and PBS, n = 10/group), SAM (80 mg/kg/day, n = 9/group), anti-PD-1 antibody (5 mg/kg, twice per week, n = 10/group), or the combination (n = 10/group). (A) Representative X-ray images showing the anatomy of the lower limb. The tibia, fibula, and femur (in part) along with the knee joint are shown. X-rays of the mice were taken at day 21 post-tumor injection. Black arrows indicate tumors, while white arrows indicate a broken cortical bone margin. (B) X-ray images were used to calculate a bone lesion score (BLS) for each group in increments from 0 to 4, where 0 represents no tumor lesions with the highest bone integrity (no breaks in the peripheral margin) and 4 represents the maximum tumor lesion area with the lowest bone integrity and with major breaks in the peripheral margin (n = 10/group, except SAM (n = 9/group)). (C) Representative histology images of mouse tibias 21 days post-tumor injection. Briefly, mice were sacrificed at day 21, and tibias were extracted, fixed, decalcified, embedded, sliced, and subjected to H&E staining, as described in Materials and Methods. T, tumor; BM, bone marrow. The black bar at the bottom left represents the scale in each image: top, 2 mm; below, 500 µm. (D) Total bone lesion area (µm2) for each group (n = 5/group). Briefly, the tumor lesion area in the whole tibia image was measured using the ImageScope annotation tool, added and plotted in GraphPad Prism. (E) Percentage of mice with bone metastasis in each group. Statistical significance was determined by (B, D) one-way ANOVA in GraphPad prism. Significance values are represented by asterisks (* p < 0.05; ** p < 0.01; **** p < 0.0001). Full article ">Figure 6
Tumors treated with the SAM and anti-PD-1 antibody combination show reduced expression of key oncogenes and pro-metastasis genes, and elevated expression of immunostimulatory genes. (A) Venn diagram (left) and MA plot (right) showing significant DEGs (p < 0.001) in SAM and anti-PD-1 antibody combination-treated Eo771 tumors versus control Eo771 tumors. Up, upregulated genes; down, downregulated genes. (B) Change in expression of significantly downregulated genes in the combination-treated versus control tumors extracted from RNA-seq data (left, n = 3/group) and validated with RT-qPCR (right, n = 4/group). The data are presented as fold change in expression in the treatment group relative to the control. The value of the control was set at 1. (C) Expression of key pro-metastatic genes MMP9 and MMP10 in human solid normal tissue and primary tumor tissue of breast cancer patients derived from GTEx and TCGA databases (n = 1391 samples) using the Xena platform. Expression values are depicted in RSEM, which is RNA-Seq by Expectation Maximization. (D) Change in expression of top significantly upregulated genes in combination-treated versus control tumors extracted from RNA-seq data (left, n = 3/group) and validated with RT-qPCR (right, n = 4/group). Data is presented as fold change in the treatment group relative to the control. The value of the control was set at 1. CTL, cytotoxic T lymphocytes; APM, antigen processing and presentation machinery. (E) Immunohistochemistry with CD8a+ T cell marker staining of Eo771 tumors treated with the combination treatment and the controls. (E, left) Representative images (lens, 40×; magnification, 400×) of the primary Eo771 tumors stained with murine antibody against CD8a+ marker (brown) from the control and SAM+anti-PD-1 antibody combination-treated tumors. The nuclei are stained blue and a CD8+ T cell is indicated by a black arrow. Enlarged images at the bottom right show the absence and presence of CD8+ T cells in the control and SAM+anti-PD-1 antibody group, respectively. (E, right) CD8a+ T cell positive staining area percentage (n = 4 samples/group). Statistical significance was determined using (C,E) T-test in GraphPad prism and (A,B,D) by Wald test with BH FDR (≤ 0.2) correction. Significance values are represented by asterisks (* p < 0.05; ** p < 0.01; **** p < 0.0001). Full article ">

20 pages, 1034 KiB

Open AccessArticle

A Retrospective, Single-Institution Experience of Bullous Pemphigoid as an Adverse Effect of Immune Checkpoint Inhibitors

by Walid Shalata, Sarah Weissmann, Sapir Itzhaki Gabay, Kim Sheva, Omar Abu Saleh, Ashraf Abu Jama, Alexander Yakobson and Keren Rouvinov

Cancers 2022, 14(21), 5451; https://doi.org/10.3390/cancers14215451 - 5 Nov 2022

Cited by 17 | Viewed by 2965

Abstract

Immune checkpoint inhibitors are a class of cancer treatment drugs that stimulate the immune system’s ability to fight tumor cells. These drugs are monoclonal antibodies targeting im-mune-inhibiting proteins on cancer cells, such as CTLA-4 and PD-1/PD-L1. Immune checkpoint inhibitors cause many immune-related adverse [...] Read more.

Immune checkpoint inhibitors are a class of cancer treatment drugs that stimulate the immune system’s ability to fight tumor cells. These drugs are monoclonal antibodies targeting im-mune-inhibiting proteins on cancer cells, such as CTLA-4 and PD-1/PD-L1. Immune checkpoint inhibitors cause many immune-related adverse events. Cutaneous toxicities are of the most common adverse effects and occur with a range of severity. Bullous Pemphigoid is a rare adverse event with a high impact on quality of life that may occur after immune checkpoint inhibitor treatment. In this article, we investigate current research on immune checkpoint inhibitors, cutaneous adverse events, and common presentations and treatments, with a specific focus on Bullous Pemphigoid, its characteristics, onset timing, and treatment. Significant findings include a negative skew in the onset of presentation. Furthermore, we describe exclusive cases. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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15 pages, 2739 KiB

Open AccessArticle

Comprehensive Genomic Profiling Reveals Clinical Associations in Response to Immune Therapy in Head and Neck Cancer

by Rika Noji, Kohki Tohyama, Takuma Kugimoto, Takeshi Kuroshima, Hideaki Hirai, Hirofumi Tomioka, Yasuyuki Michi, Akihisa Tasaki, Kazuchika Ohno, Yosuke Ariizumi, Iichiroh Onishi, Mitsukuni Suenaga, Takehiko Mori, Ryuichi Okamoto, Ryoichi Yoshimura, Masahiko Miura, Takahiro Asakage, Satoshi Miyake, Sadakatsu Ikeda, Hiroyuki Harada and Yoshihito Kano Show full author list Hide full author list

Cancers 2022, 14(14), 3476; https://doi.org/10.3390/cancers14143476 - 18 Jul 2022

Cited by 14 | Viewed by 3301

Abstract

Comprehensive genomic profiling (CGP) provides information regarding cancer-related genetic aberrations. However, its clinical utility in recurrent/metastatic head and neck cancer (R/M HNC) remains unknown. Additionally, predictive biomarkers for immune checkpoint inhibitors (ICIs) should be fully elucidated because of their low response rate. Here, [...] Read more.

Comprehensive genomic profiling (CGP) provides information regarding cancer-related genetic aberrations. However, its clinical utility in recurrent/metastatic head and neck cancer (R/M HNC) remains unknown. Additionally, predictive biomarkers for immune checkpoint inhibitors (ICIs) should be fully elucidated because of their low response rate. Here, we analyzed the clinical utility of CGP and identified predictive biomarkers that respond to ICIs in R/M HNC. We evaluated over 1100 cases of HNC using the nationwide genetic clinical database established by the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) and 54 cases in an institution-based study. The C-CAT database revealed that 23% of the cases were candidates for clinical trials, and 5% received biomarker-matched therapy, including NTRK fusion. Our institution-based study showed that 9% of SCC cases and 25% of salivary gland cancer cases received targeted agents. In SCC cases, the tumor mutational burden (TMB) high (≥10 Mut/Mb) group showed long-term survival (>2 years) in response to ICI therapy, whereas the PD-L1 combined positive score showed no significant difference in progression-free survival. In multivariate analysis, CCND1 amplification was associated with a lower response to ICIs. Our results indicate that CGP may be useful in identifying prognostic biomarkers for immunotherapy in patients with HNC. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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Figure 1
Total population and clinical utility of CGP in the C-CAT database. (A) C-CAT database included genomic information for the F1(F1CDx or F1LCDx) test and NCC Oncopanel test. Information of 29,490 patients was registered in C-CAT, with a total of 1119 patients diagnosed with R/M HNC. (B) Percentage of patients with access to treatment for comprehensive genomic profiles. VUS, a variant of uncertain significance. Full article ">Figure 2
Patient population and sequencing results at our institution. (A) Total population in R/M HNC with F1CDx or F1LCDx testing performed at our institution. All SCC patients received ICI therapy; one patient, who received both ICI and chemotherapy, was excluded to evaluate treatment efficacy. (B) Percentage of patients with access to treatment for comprehensive genomic profiles by histology. (C) The top 30 most frequently detected genetic mutations in all R/M HNC patients. TMB is indicated at the top of the graph as high (red, ≥10 Mut/Mb), intermediate (yellow, 6–9 Mut/Mb), and low (blue, ≤5 Mut/Mb). The color coding on the graph indicates histological type, smoking history, and type of mutation. (D) Frequent genes and variant types by histological type. Color coding indicates mutation type. Full article ">Figure 2 Cont.
Patient population and sequencing results at our institution. (A) Total population in R/M HNC with F1CDx or F1LCDx testing performed at our institution. All SCC patients received ICI therapy; one patient, who received both ICI and chemotherapy, was excluded to evaluate treatment efficacy. (B) Percentage of patients with access to treatment for comprehensive genomic profiles by histology. (C) The top 30 most frequently detected genetic mutations in all R/M HNC patients. TMB is indicated at the top of the graph as high (red, ≥10 Mut/Mb), intermediate (yellow, 6–9 Mut/Mb), and low (blue, ≤5 Mut/Mb). The color coding on the graph indicates histological type, smoking history, and type of mutation. (D) Frequent genes and variant types by histological type. Color coding indicates mutation type. Full article ">Figure 3
Outcomes of ICI therapy and association between TMB. (A) The Kaplan–Meier curves for progression-free survival among R/M HNSCC patients who have received ICI monotherapy to date in our department. (B) The percentage of TMB value in C-CAT and TMDU. (C) Response to ICI monotherapy in R/M HNSCC patients in the study. All 34 R/M HNSCC patients in this study had received ICI therapy. Of these, 1 patient who received ICI and chemotherapy, one patient who was not evaluable (NE) due to treatment interruption, and one patient with no detectable TMB value were excluded. For 31 patients, the waterfall plot (top) shows the best percent change from baseline in target lesions. Spider plot (bottom) showing objective response during ICI treatment. Color coding indicates TMB values; high (red, ≥10 Mut/Mb), medium (yellow, 6–9 Mut/Mb), and low (blue, ≤5 Mut/Mb). CI, confidence interval. Full article ">Figure 4
Outcomes of ICI therapy and association between other factors. (A) The Kaplan–Meier curves for progression-free survival by PD-L1 CPS value among R/M HNSCC patients who have received ICI monotherapy to date in our department. We analyzed 27 patients with measured PD L1 CPS. (B) Outcomes based on genetic alteration. Forest plots showing hazard ratios (HRs) with 95% CIs for progression-free survival (PFS). Kaplan–Meier curves for PFS in patients with CCND1 and FGF3, 4, 19 amplification or wild type group. Of the 34 R/M HNSCC patients in this study, 32 were analyzed, excluding one who received chemotherapy with ICI and one who could not be evaluated due to interruption of the first round of treatment. p-values are according to the log-rank test. HR, hazard ratio; amp, amplification; wt, wild-type. Full article ">

14 pages, 3051 KiB

Open AccessCommunication

Is the Efficacy of Adding Ramucirumab to Docetaxel Related to a History of Immune Checkpoint Inhibitors in the Real-World Clinical Practice?

by Tadashi Nishimura, Hajime Fujimoto, Tomohito Okano, Masahiro Naito, Chikashi Tsuji, Soichi Iwanaka, Yasumasa Sakakura, Taro Yasuma, Corina N. D’Alessandro-Gabazza, Yasuhiro Oomoto, Esteban C. Gabazza, Tetsu Kobayashi and Hidenori Ibata

Cancers 2022, 14(12), 2970; https://doi.org/10.3390/cancers14122970 - 16 Jun 2022

Cited by 5 | Viewed by 2227

Abstract

Reports on the efficacy of second-line treatment with cytotoxic agents after treatment with immune checkpoint inhibitors are limited. Here, we retrospectively evaluated patients in the real-world clinical practice treated with docetaxel or docetaxel plus ramucirumab. Ninety-three patients treated with docetaxel or docetaxel plus [...] Read more.

Reports on the efficacy of second-line treatment with cytotoxic agents after treatment with immune checkpoint inhibitors are limited. Here, we retrospectively evaluated patients in the real-world clinical practice treated with docetaxel or docetaxel plus ramucirumab. Ninety-three patients treated with docetaxel or docetaxel plus ramucirumab as a second- or later-line therapy were included. The patients were categorized into the following four treatment groups: docetaxel group (n = 50), docetaxel/ramucirumab group (n = 43) and pretreated (n = 45) and untreated (n = 48) with immune checkpoint inhibitor groups. The docetaxel/ramucirumab group showed an overall response rate of 57.1% in patients pretreated with immune checkpoint inhibitors and 20% in untreated patients. The docetaxel group showed an overall response rate of 15.4% in patients pretreated with immune checkpoint inhibitors and 5.0% in untreated patients. The median time-to-treatment failure and the median survival time were longer in the docetaxel/ramucirumab group than in the docetaxel group in both immune checkpoint inhibitor-pretreated and -untreated groups. There was no difference in time-to-treatment failure and overall survival between immune checkpoint inhibitor-pretreated and -untreated groups in each docetaxel and docetaxel/ramucirumab treatment group. In conclusion, our real-world data show that the addition of ramucirumab to docetaxel was superior to docetaxel monotherapy for improving time-to-treatment failure and overall survival, irrespective of previous treatment with immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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Figure 1
Study flow chart. The patients were divided into the DTX and DTX/RAM treatment groups. DTX: docetaxel. ICI: Immune checkpoint inhibitor. RAM ramucirumab. Full article ">Figure 2
The time-to-treatment failure and overall survival in all patients. The overall survival was significantly improved by the combined treatment with docetaxel and ramucirumab (DTX/RAM) compared to docetaxel (DTX) therapy alone. No difference was observed in time-to-treatment failure between both treatment groups. MST, median survival time. Full article ">Figure 3
Comparative analysis of docetaxel alone and combination therapy of docetaxel and ramucirumab in all immune checkpoint inhibitor-pretreated and -untreated patients. The time-to-treatment failure (TTF) was not significantly different between docetaxel (DTX) and docetaxel and ramucirumab (DTX/RAM) treatment groups, neither in the immune checkpoint inhibitor (ICI)-pretreated group nor in the immune checkpoint inhibitor (ICI)-untreated group. There was a significant difference in overall survival between DTX and DTX/RAM groups in the ICI-untreated group. Patients treated with DTX/RAM have a longer survival time than those treated with DTX in the ICI-pretreated group, although the difference was not significant. MST, median survival time. Full article ">Figure 4
Comparative analysis of immune checkpoint inhibitor-pretreated and -untreated patients in each docetaxel-treated and docetaxel/ramucirumab-treated group. The time-to-treatment failure and overall survival were not significantly different between checkpoint inhibitor-pretreated and –untreated patients in each docetaxel (DTX)-treated and docetaxel/ramucirumab (DTX/RAM)-treated group. Full article ">

13 pages, 5003 KiB

Open AccessEditor’s ChoiceArticle

Expression of CD47 and SIRPα Macrophage Immune-Checkpoint Pathway in Non-Small-Cell Lung Cancer

by Alexandra Giatromanolaki, Achilleas Mitrakas, Ioannis Anestopoulos, Andreas Kontosis, Ioannis M. Koukourakis, Aglaia Pappa, Mihalis I. Panayiotidis and Michael I. Koukourakis

Cancers 2022, 14(7), 1801; https://doi.org/10.3390/cancers14071801 - 1 Apr 2022

Cited by 20 | Viewed by 3919

Abstract

Background: Cancer cells escape macrophage phagocytosis by expressing the CD47 integrin-associated protein that binds to the SIRPα ligand (signal regulatory protein alpha) expressed by macrophages. Immunotherapy targeting this pathway is under clinical development. Methods: We investigated the expression of CD47/SIRPα molecules in a [...] Read more.

Background: Cancer cells escape macrophage phagocytosis by expressing the CD47 integrin-associated protein that binds to the SIRPα ligand (signal regulatory protein alpha) expressed by macrophages. Immunotherapy targeting this pathway is under clinical development. Methods: We investigated the expression of CD47/SIRPα molecules in a series of 98 NSCLCs, in parallel with the infiltration of tumor stroma by CD68+ macrophages, tumor-infiltrating lymphocytes (TILs), and PD-L1/PD-1 molecules. Results: Extensive membranous CD47 expression by cancer cells characterized 29/98 cases. SIRPα and CD68 were expressed, to a varying extent, by tumor-associated macrophages (Μφ, TAMs). A high CD68Mφ-score in inner tumor areas was linked with improved overall survival (p = 0.005); and this was independent of the stage (p = 0.02, hazard ratio 0.4). In contrast, high SIRPα expression by CD68+ TAMs (SIRPα/CD68-ratio) was linked with CD47 expression by cancer cells, low TIL-score, and poor prognosis (p = 0.02). A direct association of CD47 expression by cancer cells and the % FOXP3+ TILs (p = 0.01, r = 0.25) was also noted. Conclusions: TAMs play an important role in the prognosis of operable NSCLC. As SIRPα+ macrophages adversely affect prognosis, it is suggested that the CD47/SIRPα axis is a sound target for adjuvant immunotherapy policies, aiming to improve the cure rates in operable NSCLC. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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Figure 1
Immunhistochemistry for CD47: (a) CD47 immunostaining of normal bronchial epithelium (arrows); (b) CD47 immunostaining by alveolar epithelium (arrows); (c) Strong staining of CD47 expressed by the cellular membranes of cancer cells (arrows) in a squamous cell carcinoma of the lung; (d) Strong staining of CD47 expressed by the cellular membranes of cancer cells in lung adenocarcinoma (arrows); (e) CD47 expression by stroma fibroblasts (arrows) in the context of lack of CD47 expression by cancer cells; All images are shown at ×20 magnification. Full article ">Figure 2
Kaplan–Meier disease-specific overall survival curves stratified for: (a) CD47 expression by cancer cells; (b) SIRPα-Μφ score; (c) CD68-Mφ score, (d) SIRPα/CD68-ratio in inner tumor areas, and (e) SIRPα/CD68-ratio in the invading tumor front (neg = negative, med = medium, pts = patients. L = low, H = high). Full article ">Figure 3
Immunohistochemical images of normal lung alveolar tissue showing presence of macrophages stained for CD68 (a) and SIRPAa (b). Typical immunohistohemical images of non-small cell lung carcinomas with (c) low infiltration of the tumor stroma by CD68+ macrophages (score 1); (d) medium infiltration of the tumor stroma by CD68+ macrophages (score 2); (e) intense infiltration of the tumor stroma by CD68+ macrophages (score 3); (f) lack of SIRPα+ macrophages in the tumor stroma (score 0); (g) low infiltration of the tumor stroma by SIRPα+ macrophages (score 1); (h) intense infiltration of the tumor stroma by SIRPα+ macrophages (score 2). All images are shown at ×20 magnification. Thick arrows show areas of macrophage presence. As noted in all images CD68 and SIRPα were not expressed by cancer cells (thin arrows). Full article ">Figure 4
Association between CD47, SIRPα, CD68, and immunological parameters: (a,b) linear regression analysis between CD47 expression by cancer cells and SIRPα-Mφ score in the invading tumor front and inner tumor areas; (c) linear regression analysis between CD47 expression by cancer cells and SIRPα/CD68-ratio; (d) linear regression analysis between CD47 expression by cancer cells and the percentage of FOXP3+ TILs; (e) linear regression analysis between CD47 expression by cancer cells and FIL-score; (f) TIL-score distribution in two SIRPα/CD68-ratio groups. Full article ">

18 pages, 3300 KiB

Open AccessArticle

Association between Antibiotic Exposure and Systemic Immune Parameters in Cancer Patients Receiving Checkpoint Inhibitor Therapy

by Mitchell S. von Itzstein, Amrit S. Gonugunta, Thomas Sheffield, Jade Homsi, Jonathan E. Dowell, Andrew Y. Koh, Prithvi Raj, Farjana Fattah, Yiqing Wang, Vijay S. Basava, Shaheen Khan, Jason Y. Park, Vinita Popat, Jessica M. Saltarski, Yvonne Gloria-McCutchen, David Hsiehchen, Jared Ostmeyer, Yang Xie, Quan-Zhen Li, Edward K. Wakeland and David E. Gerber Show full author list Hide full author list

Cancers 2022, 14(5), 1327; https://doi.org/10.3390/cancers14051327 - 4 Mar 2022

Cited by 14 | Viewed by 3992

Abstract

Antibiotic administration is associated with worse clinical outcomes and changes to the gut microbiome in cancer patients receiving immune checkpoint inhibitors (ICI). However, the effects of antibiotics on systemic immune function are unknown. We, therefore, evaluated antibiotic exposure, therapeutic responses, and multiplex panels [...] Read more.

Antibiotic administration is associated with worse clinical outcomes and changes to the gut microbiome in cancer patients receiving immune checkpoint inhibitors (ICI). However, the effects of antibiotics on systemic immune function are unknown. We, therefore, evaluated antibiotic exposure, therapeutic responses, and multiplex panels of 40 serum cytokines and 124 antibodies at baseline and six weeks after ICI initiation, with p < 0.05 and false discovery rate (FDR) < 0.2 considered significant. A total of 251 patients were included, of whom the 135 (54%) who received antibiotics had lower response rates and shorter survival. Patients who received antibiotics prior to ICI initiation had modestly but significantly lower baseline levels of nucleolin, MDA5, c-reactive protein, and liver cytosol antigen type 1 (LC1) antibodies, as well as higher levels of heparin sulfate and Matrigel antibodies. After ICI initiation, antibiotic-treated patients had significantly lower levels of MDA5, CENP.B, and nucleolin antibodies. Although there were no clear differences in cytokines in the overall cohort, in the lung cancer subset (53% of the study population), we observed differences in IFN-γ, IL-8, and macrophage inflammatory proteins. In ICI-treated patients, antibiotic exposure is associated with changes in certain antibodies and cytokines. Understanding the relationship between these factors may improve the clinical management of patients receiving ICI. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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Review

Jump to: Editorial, Research, Other

21 pages, 1524 KiB

Open AccessReview

Tumor-Infiltrating Lymphocytes (TILs) in Epithelial Ovarian Cancer: Heterogeneity, Prognostic Impact, and Relationship with Immune Checkpoints

by Delphine Hudry, Solenn Le Guellec, Samuel Meignan, Stéphanie Bécourt, Camille Pasquesoone, Houssein El Hajj, Carlos Martínez-Gómez, Éric Leblanc, Fabrice Narducci and Sylvain Ladoire

Cancers 2022, 14(21), 5332; https://doi.org/10.3390/cancers14215332 - 29 Oct 2022

Cited by 15 | Viewed by 3572

Abstract

Epithelial ovarian cancers (EOC) are often diagnosed at an advanced stage with carcinomatosis and a poor prognosis. First-line treatment is based on a chemotherapy regimen combining a platinum-based drug and a taxane-based drug along with surgery. More than half of the patients will [...] Read more.

Epithelial ovarian cancers (EOC) are often diagnosed at an advanced stage with carcinomatosis and a poor prognosis. First-line treatment is based on a chemotherapy regimen combining a platinum-based drug and a taxane-based drug along with surgery. More than half of the patients will have concern about a recurrence. To improve the outcomes, new therapeutics are needed, and diverse strategies, such as immunotherapy, are currently being tested in EOC. To better understand the global immune contexture in EOC, several studies have been performed to decipher the landscape of tumor-infiltrating lymphocytes (TILs). CD8+ TILs are usually considered effective antitumor immune effectors that immune checkpoint inhibitors can potentially activate to reject tumor cells. To synthesize the knowledge of TILs in EOC, we conducted a review of studies published in MEDLINE or EMBASE in the last 10 years according to the PRISMA guidelines. The description and role of TILs in EOC prognosis are reviewed from the published data. The links between TILs, DNA repair deficiency, and ICs have been studied. Finally, this review describes the role of TILs in future immunotherapy for EOC. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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Figure 1
Schematic diagram of the selection process for the studies included in this review. Review according to Moher [<a href="#B21-cancers-14-05332" class="html-bibr">21</a>], EOC: epithelial ovarian cancer. Full article ">Figure 2
Immunologic network in EOC: (A) simplified TIL view and location; (B) Main immune checkpoints studied in EOC. Simplified diagram of the main TILs described in the articles studied in this review. T cells infiltrating the stroma or tumor epithelium are identified via CD3, and/or CD4 and CD8. The subtypes of T cells, including TH1, TH2, TH17, TFH, and TREG, are illustrated. The main immune checkpoints described in this review are represented. iTILs: intra-tumoral, sTILs: stromal, B-TILs: B tumor-infiltrating lymphocytes, TCR: T cell receptor, PD-1: programmed-death 1, PD-L1: PD-1 ligand 1, PD-L2: PD-1 ligand 2, CTLA4: cytotoxic T-lymphocyte-associated protein 4, Tim-3: T cell immunoglobulin and mucin domain-containing protein 3, and LAG-3: lymphocyte activating gene 3. Full article ">Figure 3
Synthesis of the effects of TILs on prognosis in EOC. This figure summarizes the conclusion of the articles exploring the effects of TILs on EOC prognosis, either being evaluated in HES or via the study of a surface marker. B-TILs are mostly identified using CD20. H&E: hematoxylin and eosin, and B-TILs: B tumor-infiltrating lymphocytes. Full article ">

28 pages, 1833 KiB

Open AccessReview

Checkpoint Inhibitors in Cancer Therapy: Clinical Benefits for Head and Neck Cancers

by Tobias Ettl, Matthias Grube, Daniela Schulz and Richard Josef Bauer

Cancers 2022, 14(20), 4985; https://doi.org/10.3390/cancers14204985 - 11 Oct 2022

Cited by 11 | Viewed by 3262

Abstract

Recently, considerable progress has been achieved in cancer immunotherapy. Targeted immune checkpoint therapies have been established for several forms of cancers, which resulted in a tremendous positive impact on patient survival, even in more advanced tumor stages. With a better understanding of cellular [...] Read more.

Recently, considerable progress has been achieved in cancer immunotherapy. Targeted immune checkpoint therapies have been established for several forms of cancers, which resulted in a tremendous positive impact on patient survival, even in more advanced tumor stages. With a better understanding of cellular responses to immune checkpoint therapies, it will soon be feasible to find targeted compounds which will make personalized medicine practicable. This is a great opportunity, but it also sets tremendous challenges on both the scientific and clinical aspects. Head and neck tumors evade immune surveillance through various mechanisms. They contain fewer lymphocytes (natural killer cells) than normal tissue with an accumulation of immunosuppressive regulatory T cells. Standard therapies for HNSCC, such as surgery, radiation, and chemotherapy, are becoming more advantageous by targeting immune checkpoints and employing combination therapies. The purpose of this review is to provide an overview of the expanded therapeutic options, particularly the combination of immune checkpoint inhibition with various conventional and novel therapeutics for head and neck tumor patients. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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14 pages, 2111 KiB

Open AccessReview

Oncolytic Adenoviruses: The Cold War against Cancer Finally Turns Hot

by Bryan Oronsky, Brian Gastman, Anthony P. Conley, Christopher Reid, Scott Caroen and Tony Reid

Cancers 2022, 14(19), 4701; https://doi.org/10.3390/cancers14194701 - 27 Sep 2022

Cited by 18 | Viewed by 3373

Abstract

Oncolytic viruses, colloquially referred to as “living drugs”, amplify themselves and the therapeutic transgenes that they carry to stimulate an immune response both locally and systemically. Remarkable exceptions aside, such as the recent 14-patient trial with the PD-1 inhibitor, dostarlimab, in mismatch repair [...] Read more.

Oncolytic viruses, colloquially referred to as “living drugs”, amplify themselves and the therapeutic transgenes that they carry to stimulate an immune response both locally and systemically. Remarkable exceptions aside, such as the recent 14-patient trial with the PD-1 inhibitor, dostarlimab, in mismatch repair (MMR) deficient rectal cancer, where the complete response rate was 100%, checkpoint inhibitors are not cure-alls, which suggests the need for a combination partner like oncolytic viruses to prime and augment their activity. This review focuses on adenoviruses, the most clinically investigated of all the oncolytic viruses. It covers specific design features of clinical adenoviral candidates and highlights their potential both alone and in combination with checkpoint inhibitors in clinical trials to turn immunologically “cold” and unresponsive tumors into “hotter” and more responsive ones through a domino effect. Finally, a “mix-and-match” combination of therapies based on the paradigm of the cancer-immunity cycle is proposed to augment the immune responses of oncolytic adenoviruses. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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25 pages, 1424 KiB

Open AccessReview

Incorporating Immunotherapy in the Management of Gastric Cancer: Molecular and Clinical Implications

by Alessandro Agnarelli, Viviana Vella, Mark Samuels, Panagiotis Papanastasopoulos and Georgios Giamas

Cancers 2022, 14(18), 4378; https://doi.org/10.3390/cancers14184378 - 8 Sep 2022

Cited by 8 | Viewed by 4063

Abstract

Gastric cancer has a median survival of 11 months, and this poor prognosis has not improved over the last 30 years. Recent pre-clinical data suggest that there is high tumour-related neoantigen expression in gastric cancer cells, suggesting that a clinical strategy that enhances [...] Read more.

Gastric cancer has a median survival of 11 months, and this poor prognosis has not improved over the last 30 years. Recent pre-clinical data suggest that there is high tumour-related neoantigen expression in gastric cancer cells, suggesting that a clinical strategy that enhances the host’s immune system against cancer cells may be a successful approach to improve clinical outcomes. Additionally, there has been an increasing amount of translational evidence highlighting the relevance of PD-L1 expression in gastric cancer cells, indicating that PD-1/PD-L1 inhibitors may be useful. Several molecular subgroups of gastric cancer have been identified to respond with excellent outcomes to immunotherapy, including microsatellite instable tumours, tumours bearing a high tumour mutational burden, and tumours related to a chronic EBV infection. In gastric cancer, immunotherapy has produced durable responses in chemo-refractory patients; however, most recently there has been a lot of enthusiasm as several large-scale clinical trials highlight the improved survival noted from the incorporation of immunotherapy in the first line setting for advanced gastric cancer. Our review aims to discuss current pre-clinical and clinical data supporting the innovative role of immunotherapy in gastric cancer. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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25 pages, 1363 KiB

Open AccessReview

Immune Checkpoint Inhibitors in Cancer Therapy—How to Overcome Drug Resistance?

by Yefang Lao, Daoming Shen, Weili Zhang, Rui He and Min Jiang

Cancers 2022, 14(15), 3575; https://doi.org/10.3390/cancers14153575 - 22 Jul 2022

Cited by 30 | Viewed by 4500

Abstract

Immune checkpoint inhibitors (ICIs), antagonists used to remove tumor suppression of immune cells, have been widely used in clinical settings. Their high antitumor effect makes them crucial for treating cancer after surgery, radiotherapy, chemotherapy, and targeted therapy. However, with the advent of ICIs [...] Read more.

Immune checkpoint inhibitors (ICIs), antagonists used to remove tumor suppression of immune cells, have been widely used in clinical settings. Their high antitumor effect makes them crucial for treating cancer after surgery, radiotherapy, chemotherapy, and targeted therapy. However, with the advent of ICIs and their use by a large number of patients, more clinical data have gradually shown that some cancer patients still have resistance to ICI treatment, which makes some patients unable to benefit from their antitumor effect. Therefore, it is vital to understand their antitumor and drug resistance mechanisms. In this review, we focused on the antitumor action sites and mechanisms of different types of ICIs. We then listed the main possible mechanisms of ICI resistance based on recent studies. Finally, we proposed current and future solutions for the resistance of ICIs, providing theoretical support for improving their clinical antitumor effect. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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13 pages, 475 KiB

Open AccessReview

The Effects of Physical Activity on Cancer Patients Undergoing Treatment with Immune Checkpoint Inhibitors: A Scoping Review

by Amy L. Shaver, Swapnil Sharma, Nikita Nikita, Daniel S. Lefler, Atrayee Basu-Mallick, Jennifer M. Johnson, Meghan Butryn and Grace Lu-Yao

Cancers 2021, 13(24), 6364; https://doi.org/10.3390/cancers13246364 - 18 Dec 2021

Cited by 13 | Viewed by 3301

Abstract

Background: Cancer therapies are associated with multiple adverse effects, including (but not limited to) cancer-related fatigue (CRF). Fatigue is one of the most common side effects of immune checkpoint inhibitors (ICIs), occurring in up to 25% of patients. Physical activity has been shown [...] Read more.

Background: Cancer therapies are associated with multiple adverse effects, including (but not limited to) cancer-related fatigue (CRF). Fatigue is one of the most common side effects of immune checkpoint inhibitors (ICIs), occurring in up to 25% of patients. Physical activity has been shown to help reduce CRF through modulating the immune system, and may synergistically aid in the anti-tumor effects of ICIs. This review describes the nature and scope of evidence for the effects associated with concurrent physical activity while undergoing ICI therapy. Method: Scoping review methodology was utilized to identify studies, extract data, and collate and summarize results. Results: In literature published from January 2010 through to August 2021, only one human study and three pre-clinical studies met inclusion criteria. Conclusion: Existing evidence supports that physical activity is associated with decreased treatment-related toxicities such as CRF. However, further investigation is warranted. The dearth of clinical studies illustrates the need for more research to address this question, to guide patients and their providers in the application of appropriate physical activity interventions in those patients undergoing ICI. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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22 pages, 2998 KiB

Open AccessSystematic Review

Radiomic Signatures Associated with CD8⁺ Tumour-Infiltrating Lymphocytes: A Systematic Review and Quality Assessment Study

by Syafiq Ramlee, David Hulse, Kinga Bernatowicz, Raquel Pérez-López, Evis Sala and Luigi Aloj

Cancers 2022, 14(15), 3656; https://doi.org/10.3390/cancers14153656 - 27 Jul 2022

Cited by 7 | Viewed by 4351

Abstract

The tumour immune microenvironment influences the efficacy of immune checkpoint inhibitors. Within this microenvironment are CD8-expressing tumour-infiltrating lymphocytes (CD8⁺ TILs), which are an important mediator and marker of anti-tumour response. In practice, the assessment of CD8⁺ TILs via tissue sampling involves [...] Read more.

The tumour immune microenvironment influences the efficacy of immune checkpoint inhibitors. Within this microenvironment are CD8-expressing tumour-infiltrating lymphocytes (CD8⁺ TILs), which are an important mediator and marker of anti-tumour response. In practice, the assessment of CD8⁺ TILs via tissue sampling involves logistical challenges. Radiomics, the high-throughput extraction of features from medical images, may offer a novel and non-invasive alternative. We performed a systematic review of the available literature reporting radiomic signatures associated with CD8⁺ TILs. We also aimed to evaluate the methodological quality of the identified studies using the Radiomics Quality Score (RQS) tool, and the risk of bias and applicability with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Articles were searched from inception until 31 December 2021, in three electronic databases, and screened against eligibility criteria. Twenty-seven articles were included. A wide variety of cancers have been studied. The reported radiomic signatures were heterogeneous, with very limited reproducibility between studies of the same cancer group. The overall quality of studies was found to be less than desirable (mean RQS = 33.3%), indicating a need for technical maturation. Some potential avenues for further investigation are also discussed. Full article

(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)

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Immune checkpoint inhibitors induce tumour cell death by activating pre-existing CD8+ TILs. CD8+ TILs express T cell receptors (TCRs) that recognise antigens presented by major histocompatibility complexes (MHCs) on either tumour cells or antigen-presenting cells (APCs). TCR–antigen–MHC interactions prime and activate CD8+ TILs to induce apoptosis. This interaction, however, is downregulated by the activation of immune checkpoints, for example, the binding of cell surface receptor proteins PD-L1 (programmed death-ligand 1) with PD-1 (programmed death-1), and CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) with B7 proteins. The blockade of these axes, via ICIs, allows CD8+ TILs to circumvent these inhibitory signals. Full article ">Figure 2
Boolean search used to retrieve relevant literature. Literature must contain at least one term from each set. Overlaps between sets indicate the Boolean AND operator. Search term truncations are denoted by an asterisk (*). Full article ">Figure 3
Flow diagram describing the literature selection process and the number of articles included according to the year of publication. Full article ">Figure 4
Radiomics workflow typically seen in the included studies. Imaging, biological, and clinical data were sourced from institutions and/or public repositories, before being subjected to further processing. To develop radiomic signatures, Pipeline A describes the main approach taken in the reviewed studies. Here, radiomic features were directly analysed for their association with CD8+ TILs. Features associated with CD8+ TILs were retained for radiomic signature derivation, model construction, and further evaluation. Pipeline B describes an alternate pathway where radiomic signatures were first developed by assessing the association of features with clinical variables, e.g., objective response. Signatures were then evaluated for their association with CD8+ TILs to explain, at least partially, the biological basis of the radiomic signatures. Acronyms: TCIA/TCGA = The Cancer Imaging Archive/The Cancer Genome Atlas, IHC = immunohistochemistry, RNA-seq = RNA sequencing. Full article ">Figure 5
(A) Summary of QUADAS-2 risk of bias and applicability concern assessments after arbitration between reviewers. (B) Violin plot showing the distribution of the overall RQS scores achieved by reviewed studies. (C) Average ratings for each dimension of the RQS, normalised to percentages (0% = minimum possible positive score; 100% = maximum possible positive score). Full article ">Figure 6
Some lines of inquiry for prospective investigators. Acronyms: SUV = standardised uptake value. Full article ">

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