Abstract
Peripheral CD4+CD8+ double positive (DP) T cells are a phenotypically and functionally heterogeneous population depending on their origin and pathologic context. We previously identified among tumour infiltrating lymphocytes in melanoma, a tumour-reactive MHC class-I restricted CD4lowCD8high DP αβ T-cell subpopulation with CD4-like function. In this study, we used an in-depth comparative transriptomic analysis of intra-melanoma DP T cells and CD4 and CD8 single positive (SP) T cells, to better comprehend the origin of this DP phenotype, and define the transcriptomic signature of activated DP T cells. We observed that intra-melanoma DP T cells were transcriptome-wise closer to their CD8 SP T-cell counterparts in terms of number of genes differentially expressed (97 in common with CD8 SP T cells and 15 with CD4 SP T cells) but presented hallmarks of a transition to a CD4-like functional profile (CD40LG) with a decreased cytotoxic signature (KLRC1) in favour of an increased cytokine-receptor interaction signature (IL4, IL24, IL17A…). This unleashed CD4-like program could be the results of the observed unbalanced expression of the THPOK/Runx3 transcription factors in DP T cells. Overall, this study allow us to speculate that intra-melanoma DP T cells arise from CD8 SP T cells being reprogrammed to a helper function.
Highlights
Peripheral CD4+CD8+ double positive (DP) T cells are a phenotypically and functionally heterogeneous population depending on their origin and pathologic context
DP T cells, we first conducted a paired comparison of their T Cell Receptor (TCR) Vβ repertoire with single positive CD4 and CD8 tumour infiltrating lymphocytes (TIL)
CD4lowCD8high DP, CD4 single positive (SP) and CD8 SP T cell subpopulations were isolated by FACS sorting (Supplementary Fig. S1) from 8 TILs previously established and amplified in vitro from melanoma-invaded lymph nodes[10]
Summary
Peripheral CD4+CD8+ double positive (DP) T cells are a phenotypically and functionally heterogeneous population depending on their origin and pathologic context. We observed that intra-melanoma DP T cells were transcriptome-wise closer to their CD8 SP T-cell counterparts in terms of number of genes differentially expressed (97 in common with CD8 SP T cells and 15 with CD4 SP T cells) but presented hallmarks of a transition to a CD4-like functional profile (CD40LG) with a decreased cytotoxic signature (KLRC1) in favour of an increased cytokine-receptor interaction signature (IL4, IL24, IL17A...). We have described the enrichment in the tumour infiltrate of several solid cancers including melanoma, of a class-I-restricted DP T-cell population presenting the CD4lowCD8high phenotype[9,10] This population was not increased in the peripheral blood suggesting the influence of the tumour microenvironment upon the development of DP T cells. This study suggests that intra-melanoma DP T cells could be the result of a functional plasticity of CD8 T cells following activation and exposure to the tumour microenvironment
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