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Functional state of lung cancer-reactive cytotoxic T cells is shaped during 2 T cell priming and determines sensitivity to immunotherapy

ABSTRACT: In non-small cell lung cancer (NSCLC), response to checkpoint blockade therapy (CBT) is associated with PD-L1 expression, induced by IFN-g-producing, tumor-infiltrating CD8+ T cells. However, not all tumors with a CD8+ T cell infiltrate respond to CBT, and little is known about the mechanisms governing CBT resistance in T cell-infiltrated NSCLC. We used a pre-clinical orthotopic NSCLC mouse model to study CBT-refractory CD8+ T cell responses. Single-cell RNA sequencing revealed that lung cancer-specific tumor-infiltrating CD8+ T cells exhibited clonal expansion but lacked expression of genes associated with effector and exhausted T cell responses, indicating that they underwent a differentiation program distinct from conventional T cell exhaustion. Mechanistic studies revealed that this lung cancer-specific T cell dysfunction program was established early during priming in the mediastinal lymph node. This program was characterized by robust T cell proliferation and acquisition of lung-homing factors but a failed upregulation of markers of effector and exhausted T cells. Intriguingly, CD8+ T cells from NSCLC patients expressed an analogous gene expression program which was associated with lung cancer specific T cell dysfunction and distinct from conventional T cell exhaustion. As a proof-of-concept that this lung cancer-specific T cell differentiation program could be therapeutically manipulated, we administrated recombinant IL-2 and IL-12, which was sufficient to restore effector T cell differentiation and induce control of lung tumors. These findings imply that a lung cancer-specific CD8+ T cell differentiation trajectory, activated during T cell priming in the mediastinal lymph node, limits the response of CD8+ T cells to CBT and thereby contributes to failed responses following CBT in T cell-infiltrated NSCLC.

ORGANISM(S): Mus musculus

PROVIDER: GSE184388 | GEO | 2021/09/20

REPOSITORIES: GEO

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Project description:Introduction: Tobacco smoking generates airway inflammation in chronic obstructive pulmonary disease (COPD), and its involvement in the development of lung cancer is still among the leading causes of early death. Therefore, we aimed to have a better understanding of the disbalance in immunoregulation in chronic inflammatory conditions in smoker subjects with stable COPD (stCOPD), exacerbating COPD (exCOPD), or non-small cell lung cancer (NSCLC). Methods: Smoker controls without chronic illness were recruited as controls. Through extensive mapping of single cells, surface receptor quantification was achieved by single-cell mass cytometry (CyTOF) with 29 antibodies. The CyTOF characterized 14 main immune subsets such as CD4+, CD8+, CD4+/CD8+, CD4 −/CD8−, and g/d T cells and other subsets such as CD4+ or CD8+ NKT cells, NK cells, B cells, plasmablasts, monocytes, CD11cdim, mDCs, and pDCs. The CD4+ central memory (CM) T cells (CD4+/CD45RA−/CD45RO+/CD197+) and CD4+ effector memory (EM) T cells (CD4+/CD45RA−/CD45RO+/CD197−) were FACSsorted for RNA-Seq analysis. Plasma samples were assayed by Luminex MAGPIX® for the quantitative measurement of 17 soluble immuno-oncology mediators (BTLA, CD28, CD80, CD27, CD40, CD86, CTLA-4, GITR, GITRL, HVEM, ICOS, LAG-3, PD-1, PD-L1, PD-L2, TIM-3, TLR-2) in the four studied groups. Results: Our focus was on T-cell-dependent differences in COPD and NSCLC, where peripheral CD4+ central memory and CD4+ effector memory cells showed a significant reduction in exCOPD and CD4+ CM showed elevation in NSCLC. The transcriptome analysis delineated a perfect correlation of differentially expressed genes between exacerbating COPD and NSCLCderived peripheral CD4+ CM or CD4+ EM cells. The measurement of 17 immuno-oncology soluble mediators revealed a disease-associated phenotype in the peripheral blood of stCOPD, exCOPD, and NSCLC patients. Discussion: The applied single-cell mass cytometry, the whole transcriptome profiling of peripheral CD4+ memory cells, and the quantification of 17 plasma mediators provided complex data that may contribute to the understanding of the disbalance in immune homeostasis generated or sustained by tobacco smoking in COPD and NSCLC.

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Functional state of lung cancer-reactive cytotoxic T cells is shaped during 2 T cell priming and determines sensitivity to immunotherapy

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