scholarly journals 320 Tumor cell-intrinsic signaling mediates T cell exclusion and promotes resistance to checkpoint blockade therapy in non-small cell lung cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A344-A344
Author(s):  
Elen Torres-Mejia ◽  
Kim Nguyen ◽  
Ellen Duong ◽  
Stefani Spranger
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Gene Signature ◽  
Small Cell ◽  
Small Cell Lung ◽  
T Cell Exclusion

BackgroundLung cancer is the leading cause of cancer-related death worldwide.1 Immunotherapies such as checkpoint blockade therapy (CBT) can be an effective approach to treat patients with metastatic tumors. However, only a fraction of patients is responsive to CBT treatments.2Patients with a non-T cell-infiltrated tumor microenvironment correlate with a poor response to CBT and T cell infiltration can be influenced by tumor cell-intrinsic signaling pathways.3 4 Therefore, understanding the tumor cell-intrinsic mechanisms affecting anti-tumor immune response will aid us to design better treatments for lung cancer patients. Preliminary work in our group showed that patients with non-small cell lung cancer (NSCLC) can be segregated according to the expression of a T cell gene signature into T cell-infiltrated and non-T cell-infiltrated cohorts. Using an unbiased pathway analysis, we identified that upregulation of specific gene modules significantly correlate with low expression of the T cell gene signature gene (non-T cell-infiltration). In this project, we aim to investigate how the overexpression of one specific pathway in NSCLC cells impacts the anti-tumor immune responses.MethodsWe used a lung cancer cell line derived from a KrasG12D/+ and Tp53-/- mouse (KP) to overexpressed our gene of interest (KP-A). Tumors were induced by subcutaneous or orthotopic implantation and were treated with anti-PD-L1 and anti-CTLA-4 blocking antibodies and analyzed for tumor burden. Infiltration of cytotoxic T cells and regulatory T cells were evaluated by fluorescence microscopy. Additionally, we engineered the KP-A and KP cell lines to express the model antigen SIY which allowed us to characterize tumor-specific T cell responses and utilize SIY-reactive TCR-transgenic T cells.ResultsWe identified that the overexpression of our gene of interest in KP cells impairs the response to CBT mediated by T cell exclusion from the tumor. Analyses of tumor-reactive T cells indicated that T cell activation and differentiation into effector T cells was not affected, however, effector T cells failed to infiltrate KP-A tumors. We are currently investigating the molecular mechanism whereby our gene of interest mediates T cell exclusion.ConclusionsOur results strongly suggest that tumor cell-intrinsic activation of specific pathways in NSCLC promote immune evasion and contribute to immunotherapy resistance. Understanding the molecular and immunological mechanisms mediating T cell exclusion from the lung tumor microenvironment will facilitate the development of novel combination treatment strategies for NSCLC patients.AcknowledgementsThis work was supported by a postdoctoral fellowship from the Ludwig Center at MIT’s Koch Institute for Integrative Cancer ResearchReferencesChen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer 2014;14:535–546.Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, Sakai H, Albert I, Vergnenegre A, Peters S, Syrigos K, Barlesi F, Reck M, Borghaei H, Brahmer JR, O’Byrne KJ, Geese WJ, Bhagavatheeswaran P, Rabindran SK, Kasinathan RS, Nathan FE, Ramalingam SS. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 2019;381:2020–2031.Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature 2017;541:321–330.Nguyen KB, Spranger S. Modulation of the immune microenvironment by tumor-intrinsic oncogenic signaling. J Cell Biol 2020;219.Ethics ApprovalAll mouse experiments in this study were approved by MIT’s Committee on Animal Care (CAC) - DHHS Animal Welfare Assurance # D16-00078

Master protocol to assess safety and recommended phase 2 dose of next generation NY-ESO-1–specific TCR T-cells in HLA-A*02 patients with synovial sarcoma or non-small cell lung cancer (Substudies 1 and 2).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2661-TPS2661
Author(s):  
Adam Jacob Schoenfeld ◽  
Mehmet Altan ◽  
Taofeek K. Owonikoko ◽  
Sandra P. D'Angelo ◽  
Brian H. Ladle ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Synovial Sarcoma ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Phase 2 ◽  
Next Generation ◽  
Small Cell Lung

TPS2661 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy using a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1/LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapies, such as GSK3901961 and GSK3845097, integrate added genetic modifications to enhance anticancer activity. GSK3901961 co-expresses the CD8α chain to stabilize TCR-human leukocyte A (HLA) class I interactions on CD4+ T cells, improving T-cell persistence and helper functions such as Type 1 T-helper antitumor responses. GSK3845097 co-expresses a dominant negative transforming growth factor-β (TGF-β) type II receptor to reduce TGF-β pathway activation and maintain T-cell proliferation, cytokine production, and cytotoxicity in the tumor microenvironment. A first-time-in-human master protocol (NCT04526509) will evaluate safety, tolerability, and recommended phase 2 dose (RP2D) of these and possible subsequent therapies. Substudy 1 will assess GSK3901961 in patients (pts) with advanced non-small cell lung cancer (NSCLC) or synovial sarcoma (SS). Substudy 2 will assess GSK3845097 in pts with advanced SS. Methods: Each substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage. Key inclusion criteria are age ≥18 y; measurable disease per RECIST v1.1; HLA-A*02:01, A*02:05, or A*02:06 positivity; NY-ESO-1/LAGE-1a tumor expression; advanced (metastatic/unresectable) SS with t(X;18) translocation and anthracycline-based therapy receipt/completion/intolerance (SS only); and Stage IV NSCLC, receipt of ≥1 prior line(s) of standard of care (SOC) therapy including programmed death receptor- or ligand-1 inhibitors, and SOC chemotherapy receipt/intolerance (Substudy 1 only). Key exclusion criteria are prior malignancy that is not in complete remission or clinically significant systemic illness; prior receipt of gene/NY-ESO-1–specific therapy or allogenic stem cell/solid organ transplant; central nervous system metastases (SS only); and actionable genetic aberration and receipt/failure of ≥3 systemic therapy lines (Substudy 1 only). Primary endpoints are safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints include investigator-assessed overall response rate, duration of response, and maximum expansion/persistence and phenotype of infiltrating transduced T cells. Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 or -GSK3845097 titers as applicable. Analyses will be descriptive. The substudies are enrolling. Funding: GSK (209012; NCT04526509). Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health; funded by GSK. Previously presented at AACR 2021 (CT219). Clinical trial information: NCT04526509.

scholarly journals Programmed cell death ligand-1-mediated enhancement of hexokinase 2 expression is inversely related to T-cell effector gene expression in non-small-cell lung cancer

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Sehui Kim ◽  
Ji-Young Jang ◽  
Jaemoon Koh ◽  
Dohee Kwon ◽  
Young A. Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Tumor Cells ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Metabolic Reprogramming ◽  
Small Cell Lung ◽  
Cell Effector

Abstract Background We investigated the role of PD-L1 in the metabolic reprogramming of non-small cell lung cancer (NSCLC). Methods Changes in glycolysis-related molecules and glycolytic activity were evaluated in PD-L1low and PD-L1high NSCLC cells after transfection or knockdown of PD-L1, respectively. Jurkat T-cell activation was assessed after co-culture with NSCLC cells. The association between PD-L1 and immune response-related molecules or glycolysis were analyzed in patients with NSCLC and The Cancer Genome Atlas (TCGA). Results Transfecting PD-L1 in PD-L1low cells enhanced hexokinase-2 (HK2) expression, lactate production, and extracellular acidification rates, but minimally altered GLUT1 and PKM2 expression and oxygen consumption rates. By contrast, knocking-down PD-L1 in PD-L1high cells decreased HK2 expression and glycolysis by suppressing PI3K/Akt and Erk pathways. Interferon-γ (IFNγ) secretion and activation marker expression was decreased in stimulated Jurkat T-cells when co-cultured with HK2-overexpressing vector-transfected tumor cells rather than empty vector-transfected tumor cells. Immunohistochemistry revealed that PD-L1 expression was positively correlated with HK2 expression in NSCLC (p < 0.001). In TCGA, HK2 exhibited a positive linear association with CD274 (PD-L1) expression (p < 0.001) but an inverse correlation with the expression of CD4, CD8A, and T-cell effector function-related genes in the CD274high rather than CD274low group. Consistently, there were fewer CD8+ T-cells in PD-L1positive/HK2high tumors compared to PD-L1positive/HK2low tumors in squamous cell carcinoma. Conclusions PD-L1 enhances glycolysis in NSCLC by upregulating HK2, which might dampen anti-tumor immunity. PD-L1 may contribute to NSCLC oncogenesis by inducing metabolic reprogramming and immune checkpoint.

scholarly journals 286 Sex differences in the transcriptional profiles of mucosal-associated invariant T cells in neoadjuvant anti-PD-1 treated non-small cell lung cancer (NSCLC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A310-A310
Author(s):  
Poromendro Burman ◽  
Boyang Zhang ◽  
Zhicheng Ji ◽  
Justina Caushi ◽  
Frank Housseau ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Normal Lung ◽  
Small Cell Lung ◽  
Mait Cells ◽  
Invariant T Cells

BackgroundMucosal Associated Invariant T Cells (MAIT cells) are unconventional T cells that recognize vitamin B metabolites derived from bacteria and are mainly present in mucosal tissues and peripheral blood.1 Their activation by T Cell Receptor (TCR)-dependent and -independent pathways can result in effector function that can either promote or inhibit cytotoxic effects.2 MAIT cells are known to be involved in the pathogenesis of multiple diseases that involve mucosal tissues, such as non-small cell lung cancer (NSCLC).2 Recently, studies have shown that disparate outcomes to SARS-CoV-2-infection between males and females may involve a differential activation of MAIT cells in the lung mucosa.3 It is therefore conceivable to hypothesize that sex differences of MAIT cells in NSCLC may also impact outcome, however their involvement in progression and subsequent treatment response of NSCLC has never been explored.MethodsTo study the transcriptional program of MAIT cells in NSCLC as a function of sex, peripheral blood and tissue biospecimens were obtained from the first-in-human clinical trial of neoadjuvant anti-PD-1 (nivolumab) in resectable non-small cell lung cancer; NCT02259621.4 Coupled single-cell RNAseq/TCRseq was performed on tumor infiltrating lymphocytes (TIL), paired adjacent normal lung, and tumor-draining lymph nodes (TDLN). MAIT cells were identified by expression of SLC4A10 and the invariant TRAV1-2 and TRAJ33/12/20 TCR. Computational analysis revealed 4 distinct MAIT cell clusters and differentially expressed genes in the tumors and healthy normal lung of males as compared to females.ResultsIn MAIT cells from females, we found upregulation of CD8A, GNLY, and NKG7 genes. These genes are involved with T cell activation and cytolytic function, suggesting that the activation of these genes in MAIT cells could be contributing towards their cytolytic activity in females. In MAIT cells from males, we found upregulation of PDE3B and PCBP2 genes, which are known to be involved with immunosuppression and downregulation of cytotoxic T lymphocyte (CTL) responses. These findings were consistent in the healthy normal lung, suggesting these transcriptional programs may be due to the normal lung biology and not necessarily a byproduct of carcinogenesis.ConclusionsThese results highlight the potential for dual characteristics of MAIT cells in neoadjuvant anti-PD-1-treated NSCLCs and provide an important foundation in our study of the often dichotomous responses between males and females to immunotherapy. Future analyses will focus on the interplay of MAIT cells with other cells in the tumor microenvironment (TME) as a function of immunotherapy treatment and clinical response.ReferencesChen Z, Wang H, D’Souza C, et al. Mucosal-associated invariant T-cell activation and accumulation after in vivo infection depends on microbial riboflavin synthesis and co-stimulatory signals. Mucosal Immunol 2017;10:58–68.Wen X, Zhang X, et al. Title of article: mucosal-associated invariant T cells in lung cancers. Elsevier 2021;94.Yu C, Littleton S, et al. Mucosal-associated invariant T cell responses differ by sex in COVID-19. CellPress 2021;2:755–772.Caushi JX, Zhang J, Ji Z, et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature 2021.Ethics ApprovalThis study was approved by the Institutional Review Boards (IRB) at Johns Hopkins University (JHU) and Memorial Sloan Kettering Cancer Center and was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The patients described in this study provided written informed consent.

scholarly journals The evolution of T-cell receptor repertoire in different stages of non-small cell lung cancer

2020 ◽  
Author(s):  
Ziqi Jia ◽  
Yadong Wang ◽  
Xiaoying Yang ◽  
Pancheng Wu ◽  
Yanyu Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Development ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tcr Repertoire

Abstract Background The intricate relationship between the tumor and host was not well understood, and antigen-specific T cell is fundamental in understanding the interaction. TCR repertoire analysis which described TCR clonotypes and TCR numbers has shown that TCRs with high frequency was tumor-specific T cells, while others might be ‘bystander’ T cells within tumors. However, how these “expanded” tumor-specific T cells was selected during the tumor development was not clear. Methods We retrospectively analyzed TCR sequencing and mutation sequencing results from 144 non-small cell lung cancer (NSCLC) patients. Results A rich TCR repertoire comprising thousands of different TCR sequences was identified in all stages of NSCLC, with most TCR clonotypes presented at low frequency. Interestingly, Stage IV NSCLC tumors contain more expanded TCRs as compared to earlier stages, however, lymph node metastasis or tumor size had little impact on expanded TCRs. Moreover, accumulation of mutations did not significantly change the number of TCR clonotypes, however, EGFR mutant patients had significantly lower while KRAS mutant patients had significantly higher number of TCR clonotypes especially in terms of those “expanded” TCRs. Conclusions In summary, T cells in the tumor microenvironment were gradually activated with tumor development. Critical events such as distal metastases and generation of EGFR or KRAS mutations might be the major factors affecting the changing of tumor-specific T cells in the tumor microenvironment.

scholarly journals Screening of T Cell-Related Long Noncoding RNA-MicroRNA-mRNA Regulatory Networks in Non-Small-Cell Lung Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Jinlong Duan ◽  
Yuefen Pan ◽  
Xi Yang ◽  
Liping Zhong ◽  
Yin Jin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Memory Cd4 T Cells

Background. Lung cancer (LC) has the highest mortality rate among all the other types of cancer in the world. T cells are known to be the key factor in inducing the immune response during LC. Objective. In this study, we aimed to screen and analyze RNAs associated with CD8(+) T cells and activated memory CD4(+) T cells in lung adenocarcinomas, a subtype of non-small-cell lung cancer (NSCLC-LUAD). Methods. Gene expression RNA-seq data and clinical data of NSCLC-LUAD were downloaded from the XENA database. The data were divided into low scores and high scores based on the Stromal and Immune scores. Then, all the genes were screened for identifying those specifically associated with CD8(+) T cells and activated memory CD4(+) T cells. The screened genes were used for the construction of the protein-protein interaction (PPI) network and for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis along with prognosis analysis. Based on the results of the prognostic analysis, the prognostic-related genes were used to analyze long noncoding (lnc)RNA-micro(mi)RNA-mRNA networks and to predict small chemical molecules. Results. According to the Immune and Stromal scores, a total of 885 upregulated and 29 downregulated RNAs were identified. A total of 90 differentially expressed genes (DEGs) were found to be related to CD8(+) T immune cells, and 48 DEGs were related to activated memory CD4(+) T cells. GPR174 and CD226 suggested a favorable prognosis. For CD8(+) and activated memory CD4(+) T cells, 112 and 113 PPI edges were obtained, respectively. GPR174 was found to be regulated by hsa-miR-19b-5p and hsa-miR-19b-2-5p, and both of these two miRNAs were regulated by lncRNA PCED1B-AS1. CD226 was regulated by hsa-miR-379-5p, which was in turn regulated by lncRNA RP11-81H14.2. Conclusion. Our findings provide a deeper understanding of the T cell-related ceRNA regulatory mechanism in NSCLC-LUAD pathogenesis.

scholarly journals Landscape of transcript isoforms in single T cells infiltrating in non-small cell lung cancer

2020 ◽  
Author(s):  
Jiesheng Li ◽  
Zemin Zhang ◽  
Xianwen Ren
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
T Cell Activation ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Computational Method ◽  
Small Cell Lung

ABSTRACTSingle cell RNA-seq has enabled high-resolution characterization of molecular signatures of tumor-infiltrating lymphocytes. However, analyses at the transcript isoform level are rarely reported. As alternative splicing is critical to T cell differentiation and activation, here we proposed a computational method named as IDEA to comprehensively detect and annotate differentially used isoforms across cell subtypes. We applied IDEA on a scRNA-seq dataset of 12,346 T cells from non-small cell lung cancer. We found most genes tend to dominantly express one isoform in single T cells, enabling typing T cells according to the isotypes given a gene. Isotype analysis suggested that tumor-infiltrating T cells significantly preferred specific isotypes for 245 genes in CD8+ T cells and 456 genes in CD4+ T cells. Functional annotation suggests that the preferred isoforms involved in coding/non-coding switches, transcription start site changes, gains/losses of domains and subcellular translocation. Clonal analysis revealed that isoform switching occurred during T cell activation/differentiation. Our analysis provides precise characterization of the molecular events in tumor-infiltrating T cells and sheds new lights into the regulatory mechanisms of tumor-infiltrating T cells.

scholarly journals Tumor-Infiltrating T Cells Concurrently Overexpress CD200R with Immune Checkpoints PD-1, CTLA-4, and TIM-3 in Non-Small-Cell Lung Cancer

Pathobiology ◽  
2020 ◽  
pp. 1-10
Author(s):  
Yinghan Su ◽  
Shota Yamazaki ◽  
Ryo Morisue ◽  
Jun Suzuki ◽  
Toshiaki Yoshikawa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Immune Checkpoints ◽  
Multiparameter Flow Cytometry ◽  
Phenotypic Change ◽  
Small Cell Lung

<b><i>Introduction:</i></b> CD200R has been reported to be the receptor for the immune checkpoint molecule CD200 and can transduce immune-suppressive signals. In this study, we mainly focused on the expression level of CD200R in T cells in pulmonary artery (PA) blood and non-small-cell lung cancer (NSCLC) tumor tissue. <b><i>Methods:</i></b> Immune cells were isolated from dissected tumor samples and PA blood of NSCLC patients and analyzed with multiparameter flow cytometry. The co-expression of CD200R with other immune checkpoints, including programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), was also investigated. <b><i>Results:</i></b> CD200R expression was observed on the surface of approximately 75% of T cells among tumor-infiltrating leukocytes (TILs). Compared to T cells extracted from TILs, only 55% of T cells extracted from PA blood exhibited CD200R expression. Moreover, with higher expression of CD200R, the expression of other immune checkpoints, including PD-1, CTLA-4, and TIM-3, was also increased in tumor-infiltrating T cells compared to T cells in PA blood. <b><i>Conclusions:</i></b> Our results showed that those tumors were dominated by T cells expressing CD200R together with other checkpoints, which suggests a phenotypic change after T cell infiltration into the tumor, such as T cell exhaustion.

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