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Frontiers in Lung Cancer: Immune Modulation and Targeted Therapies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 20147

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Special Issue Editors

Dr. Aaron C. Tan

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Guest Editor

National Cancer Centre, Singapore, Singapore
Interests: genetic mutations; clonal evolution; tumor heterogeneity; metastasis; therapeutic resistance
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Nick Pavlakis

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Guest Editor

Royal North Shore Hospital, Sydney, Australia
Interests: cancer therapy; non-small cell lung cancer; colorectal cancer; pancreas cancer

Special Issue Information

Dear Colleagues,

Lung cancer remains a leading cause of cancer death globally. The era of precision oncology with targeted therapies and immunotherapy with immune checkpoint inhibitors has dramatically transformed the management of patients with advanced lung cancer, leading to improved survival outcomes. There is now an expanding list of approved novel therapies, and many more with promising efficacy data from early phase clinical trials. Nevertheless, challenges remain in developing the next generation of therapies and evaluating combination approaches for lung cancer. In particular, deep tumour sequencing has allowed for a greater understanding of the complexity of lung cancer tumour biology. This Special Issue will encompass the latest advances in lung cancer research, such as novel therapeutic targets in lung cancer, the importance of molecular testing, predictive and prognostic biomarkers, intracranial efficacy of novel therapies, the optimal sequencing of therapies, the role of targeted and immunotherapies in early stage disease, and future directions for precision oncology and immunotherapy approaches to better understand tumour evolution and therapeutic resistance.

Dr. Aaron C. Tan
Prof. Dr. Nick Pavlakis
Guest Editors

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Keywords

drug development
immunotherapy
lung cancer
next-generation sequencing (NGS)
non-small cell lung cancer (NSCLC)
targeted therapy
translational genomics

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Published Papers (6 papers)

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Research

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18 pages, 3500 KiB

Open AccessArticle

Neuroendocrine Differentiation of Lung Cancer Cells Impairs the Activation of Antitumor Cytotoxic Responses in Mice

by Ricardo Fosado, Jazmín E. Soto-Hernández, Rosa Elvira Núñez-Anita, Carmen Aceves, Laura C. Berumen and Irasema Mendieta

Int. J. Mol. Sci. 2023, 24(2), 990; https://doi.org/10.3390/ijms24020990 - 4 Jan 2023

Cited by 2 | Viewed by 2801

Abstract

Lung cancer has the highest mortality among all types of cancer; during its development, cells can acquire neural and endocrine properties that affect tumor progression by releasing several factors, some acting as immunomodulators. Neuroendocrine phenotype correlates with invasiveness, metastasis, and low survival rates. This work evaluated the effect of neuroendocrine differentiation of adenocarcinoma on the mouse immune system. A549 cells were treated with FSK (forskolin) and IBMX (3-Isobutyl-1-methylxanthine) for 96 h to induce neuroendocrine differentiation (NED). Systemic effects were assessed by determining changes in circulating cytokines and immune cells of BALB/c mice immunized with PBS, undifferentiated A549 cells, or neuroendocrine A549_NED cells. A549 cells increased circulating monocytes, while CD4⁺CD8⁻ and CD4⁺CD8⁺ T cells increased in mice immunized with neuroendocrine cells. IL-2 and IL-10 increased in mice that received untreated A549 cells, suggesting that the immune system mounts a regulated response against adenocarcinoma, which did not occur with A549_NED cells. Cocultures demonstrated the cytotoxic capacity of PBMCs when confronted with A549 cells, while in the presence of neuroendocrine cells they not only were unable to show cytolytic activity, but also lost viability. Neuroendocrine differentiation seems to mount less of an immune response when injected in mice, which may contribute to the poor prognosis of cancer patients affected by this pathology. Full article

(This article belongs to the Special Issue Frontiers in Lung Cancer: Immune Modulation and Targeted Therapies)

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Figure 1

Figure 1
Morphological changes in A549 cells treated with FSK and IBMX. Undifferentiated A549 cells show normal epithelial morphology (A) whereas A549NED cells present neurite-like outgrowths 24 h after treatment with cAMP-elevating agents (B). A zoomed-in image of the cells with the largest processes observed in (B) is also included (C). The bar graph shows the average outgrowth size in treated and untreated cells (D); results are presented as the mean ± SEM (n = 3, *** p < 0.001). Full article ">Figure 2
Gene expression of neuroendocrine markers. Syn, CgA, and GAPDH were amplified by RT-PCR from cDNA of A549 cells without treatment (Ctrl), A549 treated cells (NED), and neuroblastoma SK-N-AS cells (SK) as a positive control (A). Bar graphs showing changes in the relative gene expression of Syn (B) and CgA (C) in A549 cells with or without neuroendocrine differentiation (n = 3; * p < 0.05). Full article ">Figure 3
Changes in PBMC profiles after immunization. Flow cytometric analysis of PBMC samples obtained from the different groups of mice, targeting CD68 (a monocyte/macrophage cellular marker), CD4 (a co-receptor for the T cell receptor and specific marker of T helper cells), CD8a (a co-receptor for the T cell receptor and specific marker of cytotoxic T cells), and CD335 (a cytotoxicity-activating receptor that mediates tumor cell lysis and distinguishes NK cells from other populations). The bar graphs show the percentage of CD68+ (A), CD4+ (B), CD8+ (C), double positive CD4+/CD8+ (D), and CD335+ (E) cells in PBMCs from the different groups of mice. Results are presented as the mean ± SEM (n = 4, ** p < 0.01, * p < 0.05, # p < 0.1). Full article ">Figure 4
Changes in T cell populations. Flow cytometer results from individual samples are presented; dot plots were generated from a mouse injected with PBS (A), A549 cells (B), and A549NED cells (C). Q1 contains CD4-positive cells, Q2 contains CD4/CD8 double-positive cells, Q3 encompasses CD8 positive cells, and Q4 includes cells that are negative for both CD4 and CD8. Full article ">Figure 5
Cytokine levels in immunized mice. The bar graphs show IL-2 (A), IFN-γ (B), and IL-10 (C) levels 14 and 21 days after the first immunization; data are shown in pg/mL (n = 4, * p < 0.05). Full article ">Figure 6
Adenocarcinoma and mononuclear cells after cocultures. The number of A549 (A) and A549NED (B) cells is expressed as a percentage relative to the negative control—cells without coculture. Cells were cocultured at a 1:2 ratio (A549:PBMC) with or without PBMC pre-treatment using phytohemagglutinin (PHA). Untreated (C) or PHA-activated (D) PBMC number after coculture with A549 cells is also shown, as well as the number of untreated (E) or PHA-activated (F) PBMCs after coculture with A549NED cells, all expressed as a percentage relative to the negative control. Cells were cocultured at a 1:2 ratio (A549:PBMC) (n = 3, * p < 0.05, *** p < 0.001). Full article ">Figure 7
Cellular mechanisms involved in cocultures. We illustrate the mechanisms proposed to explain our results, in which A549 cells lost viability in coculture with PHA-preactivated PBMCs, while A549NED cells had higher viability. Our results suggest that the pre-activation of cells with PHA caused the production of IL-2, a cytokine necessary for the activation of NK cells and monocytes, which exerted their effector functions on A549 cells, producing more proinflammatory cytokines; apoptosis favored the presentation of antigens mediated by monocytes and dendritic cells, allowing the activation and clonal expansion of cytotoxic T lymphocytes, which also exerted their cytolytic activity. A549NED cells, possibly through neurotransmitters such as serotonin and norepinephrine and cytokines such as IL-4, caused the polarization of T cells towards Th2 and Treg, inhibiting cytotoxic activity and secreting cytokines that favor proliferation from cancer cells, such as IL-4, IL-13, and TGF-β [<a href="#B21-ijms-24-00990" class="html-bibr">21</a>,<a href="#B52-ijms-24-00990" class="html-bibr">52</a>,<a href="#B57-ijms-24-00990" class="html-bibr">57</a>,<a href="#B60-ijms-24-00990" class="html-bibr">60</a>,<a href="#B61-ijms-24-00990" class="html-bibr">61</a>,<a href="#B62-ijms-24-00990" class="html-bibr">62</a>]. Image created on BioRender.com, licensed and published under agreement MH24DCXFXU. Full article ">

18 pages, 3250 KiB

Open AccessArticle

Clinical Implications and Molecular Characterization of Drebrin-Positive, Tumor-Infiltrating Exhausted T Cells in Lung Cancer

by Kosuke Imamura, Yusuke Tomita, Ryo Sato, Tokunori Ikeda, Shinji Iyama, Takayuki Jodai, Misako Takahashi, Akira Takaki, Kimitaka Akaike, Shohei Hamada, Shinya Sakata, Koichi Saruwatari, Sho Saeki, Koei Ikeda, Makoto Suzuki and Takuro Sakagami

Int. J. Mol. Sci. 2022, 23(22), 13723; https://doi.org/10.3390/ijms232213723 - 8 Nov 2022

Cited by 1 | Viewed by 3152

Abstract

T cells express an actin-binding protein, drebrin, which is recruited to the contact site between the T cells and antigen-presenting cells during the formation of immunological synapses. However, little is known about the clinical implications of drebrin-expressing, tumor-infiltrating lymphocytes (TILs). To address this issue, we evaluated 34 surgical specimens of pathological stage I–IIIA squamous cell lung cancer. The immune context of primary tumors was investigated using fluorescent multiplex immunohistochemistry. The high-speed scanning of whole-slide images was performed, and the tissue localization of TILs in the tumor cell nest and surrounding stroma was automatically profiled and quantified. Drebrin-expressing T cells were characterized using drebrin⁺ T cells induced in vitro and publicly available single-cell RNA sequence (scRNA-seq) database. Survival analysis using the propensity scores revealed that a high infiltration of drebrin⁺ TILs within the tumor cell nest was independently associated with short relapse-free survival and overall survival. Drebrin⁺ T cells induced in vitro co-expressed multiple exhaustion-associated molecules. The scRNA-seq analyses confirmed that the exhausted tumor-infiltrating CD8⁺ T cells specifically expressed drebrin. Our study suggests that drebrin-expressing T cells present an exhausted phenotype and that tumor-infiltrating drebrin⁺ T cells affect clinical outcomes in patients with resectable squamous cell lung cancer. Full article

(This article belongs to the Special Issue Frontiers in Lung Cancer: Immune Modulation and Targeted Therapies)

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Figure 1

Figure 1
Drebrin expression detected in peripheral T cells and schematics of TIL analysis among patients with primary squamous cell cancer. (A) Representative images of the peripheral T cells. Purified T cells from healthy donors’ peripheral blood were stained with CD3 (green), drebrin (red), and DAPI (blue). Scale bars, 50 µm. (B) Schematics of the automated spatial analysis of the TILs. Surgical tissue specimens from patients with squamous cell lung cancer (N = 34) were stained by multiplex fluorescent immunohistochemistry, and images of all the tumor areas were analyzed. TIL, tumor-infiltrating lymphocyte. Full article ">Figure 2
Distinct patterns of drebrin-expressing TILs among lung cancer patients. Representative images of drebrin+ TILs from two patients diagnosed at the same pathological stage. Pan-cytokeratin (blue) of tumor cells, CD3 (green), and drebrin (red) were simultaneously stained. Drebrin+ or drebrin− TILs are shown at a high magnification. TILs, tumor-infiltrating lymphocytes. Full article ">Figure 3
Association of drebrin-expressing TILs in tumor cell nests and survival outcomes. (A) Relapse-free survival of patients with high and low infiltrations of drebrin+ TILs. (B) Overall survival of patients with high and low infiltrations of drebrin+ TILs. TILs, tumor-infiltrating lymphocytes. Full article ">Figure 4
Long−term T cell stimulation increases drebrin expression. (A) Frequencies of drebrin+ TILs in tumor cell nests or the surrounding stroma. (B) Assessment of drebrin expression according to the culture period with or without stimulation by flow cytometric analysis. (C) Drebrin expression of each culture period by western blot analysis. Hela cells were used as a positive control. (D) Representative images of stimulated or unstimulated T cells (96 h) stained with CD3 (green), drebrin (red), and DAPI (blue). Scale bars, 50 µm. (E) Representative histograms of stimulated or unstimulated T cells (96 h) by flow cytometric analysis. (F) Frequency of drebrin+ T cells among stimulated or unstimulated T cells (96 h). TILs, tumor-infiltrating lymphocytes. Full article ">Figure 5
Drebrin+ T cells co-express multiple exhaustion-associated molecules. (A) Representative flow cytometry plots of three populations. Triple-negative T cells are negative for PD-1, TIM-3, and LAG-3. PD-1 positive T cells are positive for PD-1 but negative for TIM-3 and LAG-3. Triple-positive T cells are positive for PD-1, TIM-3, and LAG-3. Cells were cultured for 96 h. (B) Representative histograms of each population. (C) Frequencies of drebrin+ T cells among each population. (D) A correlation between drebrin expression in T cells and triple-positive T cells under in vitro culture conditions. Cells were cultured for up to 96 h. (E) Representative histograms of triple-positive or triple-negative T cells. (F) Frequencies of CXCL13+ T cells among each population. Cells were cultured for 96 h. (G) Representative histograms of drebrin-positive or drebrin-negative T cells. (H) Frequencies of CXCL13+ T cells among each population. Cells were cultured for 96 h. CXCL13, chemokine ligand 13; LAG-3, lymphocyte activation gene 3; PD-1, programmed cell death-1; TIM-3, T cell immunoglobulin- and mucin-domain-containing protein 3. Full article ">Figure 6
Transcriptional characterization of drebrin+ T cells in NSCLC patients. (A) Comparison of drebrin1 levels between CD4+ and CD8+ T cells. Each dot represents one cell. (B) Comparison of drebrin1 levels between different tissue samples. Each dot represents one cell. (C) Expressions of drebrin1 and CXCL13 in T cells from the tumor are illustrated in the t-SNE plots. Each dot represents one cell. (D) Expressions of drebrin1 and CXCL13 in each cluster are illustrated in violin plots. Each dot represents one cell. The definition of each cluster is indicated on the right panel. Intermediate cells represent cells bridging naïve, effector, and exhausted clusters. MAIT, mucosal-associated invariant T cells; NSCLC, non-small-cell lung cancer; t-SNE, t-distributed stochastic neighbor embedding. Full article ">

15 pages, 1697 KiB

Open AccessArticle

Technical Validation and Clinical Implications of Ultrasensitive PCR Approaches for EGFR-Thr790Met Mutation Detection in Pretreatment FFPE Samples and in Liquid Biopsies from Non-Small Cell Lung Cancer Patients

by Javier Simarro, Gema Pérez-Simó, Nuria Mancheño, Emilio Ansotegui, Carlos Francisco Muñoz-Núñez, José Gómez-Codina, Óscar Juan and Sarai Palanca

Int. J. Mol. Sci. 2022, 23(15), 8526; https://doi.org/10.3390/ijms23158526 - 31 Jul 2022

Cited by 3 | Viewed by 2486

Abstract

In pretreatment tumor samples of EGFR-mutated non-small cell lung cancer (NSCLC) patients, EGFR-Thr790Met mutation has been detected in a variable prevalence by different ultrasensitive assays with controversial prognostic value. Furthermore, its detection in liquid biopsy (LB) samples remains challenging, being hampered by the shortage of circulating tumor DNA (ctDNA). Here, we describe the technical validation and clinical implications of a real-time PCR with peptide nucleic acid (PNA-Clamp) and digital droplet PCR (ddPCR) for EGFR-Thr790Met detection in diagnosis FFPE samples and in LB. Limit of blank (LOB) and limit of detection (LOD) were established by analyzing negative and low variant allele frequency (VAF) FFPE and LB specimens. In a cohort of 78 FFPE samples, both techniques showed an overall agreement (OA) of 94.20%. EGFR-Thr790Met was detected in 26.47% of cases and was associated with better progression-free survival (PFS) (16.83 ± 7.76 vs. 11.47 ± 1.83 months; p = 0.047). In LB, ddPCR was implemented in routine diagnostics under UNE-EN ISO 15189:2013 accreditation, increasing the detection rate of 32.43% by conventional methods up to 45.95%. During follow-up, ddPCR detected EGFR-Thr790Met up to 7 months before radiological progression. Extensively validated ultrasensitive assays might decipher the utility of pretreatment EGFR-Thr790Met and improve its detection rate in LB studies, even anticipating radiological progression. Full article

(This article belongs to the Special Issue Frontiers in Lung Cancer: Immune Modulation and Targeted Therapies)

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Figure 1

Figure 1
Correlation between theoretical VAF (%) and observed VAF (%) by ddPCR. Observed values are the mean of two independent experiments with error bars representing the standard deviation. Logarithmic transformation of both variables was applied to enhance visualization. Full article ">Figure 2
ddPCR and PNA Clamp TaqMan assays results for 78 FFPE specimens. Each symbol represents one sample whose position is determined by PNA Clamp TaqMan assay result (X-axis) and ddPCR assay result (Y-axis). Gray bars represent uncertainty zone of each methodology which is limited by LOB and LOD values. (●) Samples with concordant results, (○) samples in uncertainty area and (∆) samples with discordant results. Positive samples with VAF higher than 0.3% are not depicted. Full article ">Figure 3
Duration of progression-free survival according to consensus EGFR-Thr790Met pretreatment status determined by PNA Clamp TaqMan Assay and ddPCR. HR: Hazard ratio, CI: Confidence interval. Full article ">Figure 4
Increase in EGFR-Thr790Met prevalence at the time of disease progression according to different testing strategies. A: Cobas®, B: ddPCR—peripheral blood, C: ddPCR—peripheral blood + ddPCR—other body fluids and D: Strategy C + second tissue biopsies. Prevalence obtained with each strategy is depicted. Full article ">Figure 5
Dynamics of EGFR-Thr790Met mutation detected by ddPCR during follow-up in NSCLC patients treated with EGFR-TKI. Patients A and B (A,B). Red dots represent the EGFR-Thr790Met copies/mL of plasma detected in each sample. Molecular progression and radiological progression are depicted. Light red filled area comprises the months between these moments. Full article ">Figure 6
Flow chart showing the patients included in the pretreatment cohort. NSCLC: Non-small cell lung cancer. EGFR-TKI: Epidermal growth factor receptor tyrosine kinase inhibitor. Full article ">

Review

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18 pages, 728 KiB

Open AccessReview

Unraveling the Impact of Intratumoral Heterogeneity on EGFR Tyrosine Kinase Inhibitor Resistance in EGFR-Mutated NSCLC

by Keigo Kobayashi and Aaron C. Tan

Int. J. Mol. Sci. 2023, 24(4), 4126; https://doi.org/10.3390/ijms24044126 - 18 Feb 2023

Cited by 5 | Viewed by 3550

Abstract

The advent of tyrosine kinase inhibitors (TKIs) for treating epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) has been a game changer in lung cancer therapy. However, patients often develop resistance to the drugs within a few years. Despite numerous studies that have explored resistance mechanisms, particularly in regards to collateral signal pathway activation, the underlying biology of resistance remains largely unknown. This review focuses on the resistance mechanisms of EGFR-mutated NSCLC from the standpoint of intratumoral heterogeneity, as the biological mechanisms behind resistance are diverse and largely unclear. There exist various subclonal tumor populations in an individual tumor. For lung cancer patients, drug-tolerant persister (DTP) cell populations may have a pivotal role in accelerating the evolution of tumor resistance to treatment through neutral selection. Cancer cells undergo various changes to adapt to the new tumor microenvironment caused by drug exposure. DTP cells may play a crucial role in this adaptation and may be fundamental in mechanisms of resistance. Intratumoral heterogeneity may also be precipitated by DNA gains and losses through chromosomal instability, and the role of extrachromosomal DNA (ecDNA) may play an important role. Significantly, ecDNA can increase oncogene copy number alterations and enhance intratumoral heterogeneity more effectively than chromosomal instability. Additionally, advances in comprehensive genomic profiling have given us insights into various mutations and concurrent genetic alterations other than EGFR mutations, inducing primary resistance in the context of tumor heterogeneity. Understanding the mechanisms of resistance is clinically crucial since these molecular interlayers in cancer-resistance mechanisms may help to devise novel and individualized anticancer therapeutic approaches. Full article

(This article belongs to the Special Issue Frontiers in Lung Cancer: Immune Modulation and Targeted Therapies)

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13 pages, 1165 KiB

Open AccessReview

Anti-Angiogenic Therapy in ALK Rearranged Non-Small Cell Lung Cancer (NSCLC)

by Aaron C. Tan and Nick Pavlakis

Int. J. Mol. Sci. 2022, 23(16), 8863; https://doi.org/10.3390/ijms23168863 - 9 Aug 2022

Cited by 6 | Viewed by 4149

Abstract

The management of advanced lung cancer has been transformed with the identification of targetable oncogenic driver alterations. This includes anaplastic lymphoma kinase (ALK) gene rearrangements. ALK tyrosine kinase inhibitors (TKI) are established first-line treatment options in advanced ALK rearranged non-small cell lung cancer (NSCLC), with several next-generation ALK TKIs (alectinib, brigatinib, ensartinib and lorlatinib) demonstrating survival benefit compared with the first-generation ALK TKI crizotinib. Still, despite high objective response rates and durable progression-free survival, drug resistance inevitably ensues, and treatment options beyond ALK TKI are predominantly limited to cytotoxic chemotherapy. Anti-angiogenic therapy targeting the vascular endothelial growth factor (VEGF) signaling pathway has shown efficacy in combination with platinum-doublet chemotherapy in advanced NSCLC without a driver alteration, and with EGFR TKI in advanced EGFR mutated NSCLC. The role for anti-angiogenic therapy in ALK rearranged NSCLC, however, remains to be elucidated. This review will discuss the pre-clinical rationale, clinical trial evidence to date, and future directions to evaluate anti-angiogenic therapy in ALK rearranged NSCLC. Full article

(This article belongs to the Special Issue Frontiers in Lung Cancer: Immune Modulation and Targeted Therapies)

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15 pages, 1687 KiB

Open AccessReview

TLR/WNT: A Novel Relationship in Immunomodulation of Lung Cancer

by Aina Martín-Medina, Noemi Cerón-Pisa, Esther Martinez-Font, Hanaa Shafiek, Antònia Obrador-Hevia, Jaume Sauleda and Amanda Iglesias

Int. J. Mol. Sci. 2022, 23(12), 6539; https://doi.org/10.3390/ijms23126539 - 11 Jun 2022

Cited by 13 | Viewed by 2923

Abstract

The most frequent cause of death by cancer worldwide is lung cancer, and the 5-year survival rate is still very poor for patients with advanced stage. Understanding the crosstalk between the signaling pathways that are involved in disease, especially in metastasis, is crucial to developing new targeted therapies. Toll-like receptors (TLRs) are master regulators of the immune responses, and their dysregulation in lung cancer is linked to immune escape and promotes tumor malignancy by facilitating angiogenesis and proliferation. On the other hand, over-activation of the WNT signaling pathway has been reported in lung cancer and is also associated with tumor metastasis via induction of Epithelial-to-mesenchymal-transition (EMT)-like processes. An interaction between both TLRs and the WNT pathway was discovered recently as it was found that the TLR pathway can be activated by WNT ligands in the tumor microenvironment; however, the implications of such interactions in the context of lung cancer have not been discussed yet. Here, we offer an overview of the interaction of TLR-WNT in the lung and its potential implications and role in the oncogenic process. Full article

(This article belongs to the Special Issue Frontiers in Lung Cancer: Immune Modulation and Targeted Therapies)

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