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Project description:Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but most patients do not respond. PD-1 blockade “unleashes” CD8 T cells, including those specific for mutation-associated neoantigens (MANA), but factors in the tumor microenvironment can inhibit responses by dampening MANA-specific T cell function. Recent advances in single cell transcriptomics are revealing global T cell dysfunction programs in tumor-infiltrating lymphocytes (TIL). However, the vast majority of TIL do not recognize tumor antigens and little is known about transcriptional programs of true MANA-specific TIL. Here, we use an integrated approach to identify MANA-specific T cell clones using the MANA functional expansion of specific T cells (MANAFEST) assay in neoadjuvant anti-PD-1-treated lung cancers and use their TCR CDR3 as barcodes to track them and analyze their transcriptional programs and function in the tumor microenvironment using single cell RNA sequencing. We find both MANA-and virus-specific clones in TIL and adjacent normal lung, regardless of response status. MANA-specific, influenza (flu)-specific and EBV-specific TIL each have unique transcriptional programs. Most MANA-specific clones are tissue resident memory (TRM) cells, an incompletely activated cytolytic program, including EOMES deficiency, and higher levels of genes encoding T cell inhibitory molecules and Tox2. Notably, MANA-specific T cells express low levels of IL-7R and are functionally less responsive to IL-7 compared with tissue-resident flu-specific clones. MANA-specific clones from anti-PD-1 non-responding tumors express TCR with markedly lower ligand-dependent signaling capability, are largely confined to HOBIThi TRM subsets and coordinately up-regulate genes encoding specific checkpoints, killer inhibitory receptors, and intracellular inhibitors of T cell activation and cytotoxicity. These findings provide mechanistic and potential therapeutic insights into overcoming resistance to PD-1 blockade.
2021-07-21 | GSE176022 | GEO
Project description:Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but most patients do not respond. PD-1 blockade “unleashes” CD8 T cells, including those specific for mutation-associated neoantigens (MANA), but factors in the tumor microenvironment can inhibit responses by dampening MANA-specific T cell function. Recent advances in single cell transcriptomics are revealing global T cell dysfunction programs in tumor-infiltrating lymphocytes (TIL). However, the vast majority of TIL do not recognize tumor antigens and little is known about transcriptional programs of true MANA-specific TIL. Here, we use an integrated approach to identify MANA-specific T cell clones using the MANA functional expansion of specific T cells (MANAFEST) assay in neoadjuvant anti-PD-1-treated lung cancers and use their TCR CDR3 as barcodes to track them and analyze their transcriptional programs and function in the tumor microenvironment using single cell RNA sequencing. We find both MANA-and virus-specific clones in TIL and adjacent normal lung, regardless of response status. MANA-specific, influenza (flu)-specific and EBV-specific TIL each have unique transcriptional programs. Most MANA-specific clones are tissue resident memory (TRM) cells, an incompletely activated cytolytic program, including EOMES deficiency, and higher levels of genes encoding T cell inhibitory molecules and Tox2. Notably, MANA-specific T cells express low levels of IL-7R and are functionally less responsive to IL-7 compared with tissue-resident flu-specific clones. MANA-specific clones from anti-PD-1 non-responding tumors express TCR with markedly lower ligand-dependent signaling capability, are largely confined to HOBIThi TRM subsets and coordinately up-regulate genes encoding specific checkpoints, killer inhibitory receptors, and intracellular inhibitors of T cell activation and cytotoxicity. These findings provide mechanistic and potential therapeutic insights into overcoming resistance to PD-1 blockade.
2021-07-21 | GSE176021 | GEO
Project description:PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a 'barcode' to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein-Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.
| S-EPMC8338555 | biostudies-literature
Project description:Distinct transcriptional programs characterize neoantigen-specific T cells in lung cancers treated with neoadjuvant PD-1 blockade
| PRJNA725225 | ENA
Project description:Distinct transcriptional programs characterize neoantigen-specific T cells in lung cancers treated with neoadjuvant PD-1 blockade [bulk TCR-seq]
| PRJNA734593 | ENA
Project description:Distinct transcriptional programs characterize neoantigen-specific T cells in lung cancers treated with neoadjuvant PD-1 blockade [single-cell RNA-seq]
| PRJNA734597 | ENA
Project description:BACKGROUND:Antibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. METHODS:In this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses. RESULTS:Neoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. CONCLUSIONS:Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood. (Funded by Cancer Research Institute-Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621 .).
| S-EPMC6223617 | biostudies-literature
Project description:We study the expression profile of MANA-specific T cells, we used the MANA functional expansion of specific T cells (MANAFEST) assay in neoadjuvant anti-PD-1-treated lung cancers and applied their T cell receptor’s (TCR) complementarity-determining region 3 (CDR3) as a “barcode†to track and analyze their transcriptional programs in the tumor microenvironment using single cell TCR sequencing coupled with single cell RNA sequencing. We revealed distinct phenotype for MANA- and virus-specific clones in TIL and adjacent normal lung, regardless of response. MANA-specific T cells show features that drive the differences between responders and non-responders.
| EGAS00001005343 | EGA
Project description:Several clinical trials have shown the safety and effectiveness of PD-1/PD-L1 inhibitors in neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC). However, 18-83% patients can benefit from it. In this study, we aimed to assess the association of PD-L1 expression, tumor mutation burden, copy number alteration (CNA, including copy number gain and loss) burden with the pathologic response to neoadjuvant PD-1 blockade and investigate the changes in the tumor immune microenvironment (TIME) during neoadjuvant immunotherapy in NSCLC. Pre-immunotherapy treatment tumor samples from twenty-nine NSCLC patients who received neoadjuvant immunotherapy with sintilimab, an anti-PD-1 drug, were subjected to targeted DNA sequencing and PD-L1 immunochemistry staining. The pathological response was positively correlated with tumor proportion score (TPS) of PD-L1 and negatively correlated with copy number gain (CNgain) burden. Of note, the combination of CNgain burden and TPS can better stratify major pathological response (MPR) patients than did CNgain or TPS alone. Whereas, TMB showed a limited correlation with pathological regression. Additionally, PD-1 blockade led to an increase in CD8+PD-1-T cells which was clinically relevant to MPR as evaluated by multiplex immunofluorescence. A significant reduction in CD19+ cells was observed in the Non-MPR group but not in the MPR group, indicating the involvement of B cells in improving neoadjuvant immunotherapy response in NSCLC. Together, our study provides new data for the correlation of PD-L1 expression and genomic factors with drug response in neoadjuvant immunotherapy settings in NSCLC. The changes of TIME may provide novel insight into the immune responses to neoadjuvant anti-PD-1 therapy.
| S-EPMC8758728 | biostudies-literature
Project description:Evidence from mouse chronic viral infection models suggests that CD8+ T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8+ T lymphocyte populations with high (PD-1T), intermediate (PD-1N) and no PD-1 expression (PD-1-) from non-small-cell lung cancer patients. PD-1T T cells showed a markedly different transcriptional and metabolic profile from PD-1N and PD-1- lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1T lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1T cells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention.
| S-EPMC6110381 | biostudies-literature