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Abstract
Checkpoint inhibitors target the inhibitory receptors expressed by tumor-infiltrating T cells in order to reinvigorate an anti-tumor immune response. Therefore, understanding T cell composition and phenotype in human tumors is crucial. We analyzed by flow cytometry tumor-infiltrating lymphocytes (TILs) from two independent cohorts of patients with different cancer types, including RCC, lung, and colon cancer. In healthy donors, peripheral T cells are usually either CD4+ or CD8+ with a small percentage of CD4+ CD8+ DP cells (<5%). Compared to several other cancer types, including lung, and colorectal cancers, TILs from about a third of RCC patients showed an increased proportion of DP CD4+CD8+ T cells (>5%, reaching 30–50% of T cells in some patients). These DP T cells have an effector memory phenotype and express CD38, 4-1BB, and HLA-DR, suggesting antigen-driven expansion. In fact, TCR sequencing analysis revealed a high degree of clonality in DP T cells. Additionally, there were high levels of PD-1 and TIM-3 expression on DP T cells, which correlated with higher expression of PD-1 and TIM-3 in conventional single positive CD8 T cells from the same patients. These results suggest that DP T cells could be dysfunctional tumor-specific T cells with the potential to be reactivated by checkpoint inhibitors.
Highlights
Checkpoint inhibitors target inhibitory receptors expressed by tumor-infiltrating T cells in order to reinvigorate an anti-tumor immune response
CD4+CD8+ DP T cells represented less than 2% of T cells in a majority of tumor samples, frequencies of CD4+CD8+ DP T cells above 5% of T cells were observed in 6/21 of RCC samples, 1/16 lung cancer and 1/16 colorectal cancer (CRC) samples (Figure 1B)
CD4 and CD8 median fluorescence intensity (MFI) in DP T cells were normalized to CD4 and CD8 MFI of conventional CD4 and CD8 T cells from the same samples, respectively, for comparison
Summary
Checkpoint inhibitors target inhibitory receptors expressed by tumor-infiltrating T cells in order to reinvigorate an anti-tumor immune response. Despite unprecedented response rates to anti-CTLA4 and anti-PD-1/PDL1 agents in some types of advanced cancers such as melanoma or non-small cell lung cancer [1,2,3,4], responses across tumor types are highly variable [5]. For the therapy to be effective, there presumably have to be indications that the targeted pathway is engaged [PDL1 expression in tumor samples [4] or PD-1 expression by T cells [7] for instance]. Even tumor-infiltrating CD8 T cells are a highly heterogeneous subset [8]. A better understanding of the heterogeneity of tumor-infiltrating T cell function and phenotype across tumor types is crucial to guide therapies and tumor selection for better response rates
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