Dysfunctional CD8+ T cells form a proliferative, dynamically regulated compartment within human melanoma
By Hanjie Li, A. M. van der Leun, Ido Yofe, Yaniv Lubling, Dikla Gelbard Solodkin, A. V. Van Akkooi, M. van den Braber, Lisette Rozeman, J. Haanen, C. Blank and 8 more. Cell, 2018
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Tumor immune cell compositions play a major role in response to immunotherapy but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here we identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector “transitional” into a dysfunctional T cell state. CD8 T cells that express a complete cytotoxic gene set are rare, and TCR sharing data suggest their independence from the transitional and dysfunctional cell states. Notably, we demonstrate that dysfunctional T cells are the major intratumoral proliferating immune cell compartment and that the intensity of the dysfunctional signature is associated with tumor-reactivity. Our data demonstrate that CD8 T cells previously defined as exhausted, are in fact a highly proliferating, clonal and dynamically differentiating cell population within the human tumor microenvironment.
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/ebbf27660eab34ab9571a7472356af83aeb98c8c
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Citations in the corpus
- Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020, background): “Similar effector and exhausted T cells, which have the highest proliferative capacity among T cell subsets, were observed in other cancers (Figure S4C) (Guo et al., 2018; Li et al., 2019; Savas et al., 2018; Thommen et al., 2018; Tirosh et al., 2016a; Zheng et al., 2017).”
- MetaCell: analysis of single-cell RNA-seq data using K-nn graph partitions (2019, methodology): “The utility of the approach was recently demonstrated in scenarios involving analysis of mammalian hematopoiesis differentiation [31], immuno-therapy [32], blood cancer [33], and inference of cell type decompositions in comparative whole organism scRNA-seq [34, 35].”
- Pan-cancer single-cell landscape of tumor-infiltrating T cells (2021, background): “In melanoma patients, CD8 tumor-infiltrating T cells exhibit a linear and continuous progression frompredysfunctional cell state to dysfunction (2), but in lung cancer patients, there are two pre-exhaustion states that could develop to exhaustion (3).”
- Cytotoxic CD8+ T cells in cancer and cancer immunotherapy (2020, background): “Furthermore, exhausted CD8 T cells retain their mitotic activity and contribute to creating or sustaining a suppressive environment.(26)”
- T follicular helper cell biology: A decade of discovery and diseases (2019, background): “Similar cells have been observed in melanoma tumors (Li et al., 2019).”