Search

Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients with non-small cell lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells are enriched for exhausted CD8+ T cells, regulatory CD4+ T cells (Treg), and follicular helper CD4+ T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, reveals that TFH and tumor-specific exhausted CD8+ T cells are clonally linked to TCF7 + SELL + progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8+ T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8+ and CD4+ T cell clones reveals persistence in the peripheral blood for years after ICB therapy. [Display omitted] • Single-cell RNA/TCR-seq with deep intra-patient, regional resolution in NSCLC • TFH, Treg, and CD8+ T cell subsets undergo progressive exhaustion with tumor proximity • LN TCF7 + progenitor exhausted T cells are clonally linked to tumor exhausted T cells • Tumor-specific T cells in aggregate persist after ICB Pai et al. report a single T cell lung cancer dataset allowing for the lineage tracing of T cells across tumor regions, lymph nodes, and peripheral blood. This resource reveals clonal linkage of antigen-specific TCF7 + SELL + progenitor exhausted cells in the lymph node and their exhausted counterparts in the tumor, and long-term peripheral persistence of these cells after checkpoint blockade. [ABSTRACT FROM AUTHOR]

Improved identification of anti-tumor T cells is needed to advance cancer immunotherapies. CD39 expression is a promising surrogate of tumor-reactive CD8+ T cells. Here, we comprehensively profiled CD39 expression in human lung cancer. CD39 expression enriched for CD8+ T cells with features of exhaustion, tumor reactivity, and clonal expansion. Flow cytometry of 440 lung cancer biospecimens revealed weak association between CD39+ CD8+ T cells and tumoral features, such as programmed death-ligand 1 (PD-L1), tumor mutation burden, and driver mutations. Immune checkpoint blockade (ICB), but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8+ T cells. Higher baseline frequency of CD39+ CD8+ T cells conferred improved clinical outcomes from ICB therapy. Furthermore, a gene signature of CD39+ CD8+ T cells predicted benefit from ICB, but not chemotherapy, in a phase III clinical trial of non-small cell lung cancer. These findings highlight CD39 as a proxy of tumor-reactive CD8+ T cells in human lung cancer. • CD39+ CD8+ T cells express features of exhaustion and tumor reactivity • CD39 expression enriches for CD8+ TCRs with tumor reactivity • CD39 expression on CD8+ T cells is non-redundant to tumor-based biomarkers • CD39+ CD8+ T cells are predictive of benefit from ICB Factors predicting benefit of immune checkpoint blockade (ICB) are needed. Here, Chow et al. demonstrate that CD39 expression marks tumor-reactive CD8+ T cells. High baseline levels of CD39+ CD8+ T cells are associated with ICB efficacy in lung cancer. Thus, CD39 is a potential tumor-extrinsic biomarker for guiding cancer management. [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1 , NEUROD1 , and POU2F3 (SCLC-A, -N, and -P, respectively). To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2 -high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2- high subpopulation. [Display omitted] • Most small cell lung cancer (SCLC) tumors share a small PLCG2 -high subpopulation • This PLCG2 -high SCLC subpopulation is linked to metastasis and poor prognosis • SCLC is enriched in profibrotic and immunosuppressive monocytes/macrophages • The presence of myeloid cells is associated with the PLCG2 -high SCLC subpopulation Chan et al. use single-cell transcriptome sequencing and imaging techniques to study the heterogeneity and tumor microenvironment of clinical small cell lung cancer specimens. This analysis identifies a PLCG2 -high-expressing subpopulation linked to metastasis and poor prognosis, and an enrichment of a monocyte/macrophage population with a profibrotic, immunosuppressive phenotype. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) has been a remarkable clinical advance for cancer; however, the majority of patients do not respond to ICB therapy. We show that metastatic disease in the pleural and peritoneal cavities is associated with poor clinical outcomes after ICB therapy. Cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), and this is associated with reduced numbers of CD8+ T cells with tumor-reactive features in pleural effusions and peritoneal ascites from patients with cancer. We mechanistically demonstrate that viable and cytotoxic anti-tumor CD8+ T cells upregulate PS and this renders them susceptible to sequestration away from tumor targets and proliferation suppression by Tim-4+ macrophages. Tim-4 blockade abrogates this sequestration and proliferation suppression and enhances anti-tumor efficacy in models of anti-PD-1 therapy and adoptive T cell therapy in mice. Thus, Tim-4+ cavity-resident macrophages limit the efficacy of immunotherapies in these microenvironments. [Display omitted] • Metastatic involvement of the serous body cavities portends worse ICB outcomes • Tim-4 levels on human macrophages correlate with reduced CD8+ CD39+ T cells • Tim-4+ macrophages sequester and impair proliferation of CD8+ T cells • Tim-4 blockade enhances the efficacy of ICB and adoptive T cell therapy in mice Chow et al. demonstrate that metastatic involvement of the pleural and peritoneal cavities is associated with poor ICB efficacy in patients with cancer. Tim-4+ cavity-resident macrophages directly impair CD8 T cell function, and Tim-4 blockade enhances the efficacy of ICB and adoptive T cell therapy in mice. [ABSTRACT FROM AUTHOR]