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Dissecting immune cell heterogeneity in human melanoma by single-cell RNA-seq

Hanjie Li  Ido Yofe  Anne Leun  Yaniv Lubling  Assaf Weiner  Alexander Akkooi  Amos Tanay  Ton Schumacher  Ido Amit  
【摘要】:Immunotherapies that aim to reactivate anti-tumor immune responses have revolutionized cancer treatment. However, the success of immunotherapy is also eclipsed by several grand challenges, including low response rate, intrinsic/acquired resistance, etc. Recent findings suggest that tumor immune infiltrates are highly heterogeneous among patients, very likely contributing to differential therapy outcomes. Therefore, characterizing and understanding such heterogeneity is critical to develop more effective immunotherapies for a wider range of patients. Here, we leveraged the power of single cell RNA-seq to characterize the tumor immune cell heterogeneity from a cohort of 25 melanoma patients and generated an unbiased map of the expression signatures of immune cells. In parallel, we also derived the T cell receptor sequences for single T cells, and determined intra-and inter-tumoral T cell clonality and inferred the functionality of clonally expanded T cell populations in the tumor. Different cell types and cellular states were observed, including na?ve, cytotoxic, dysfunctional, memory, and regulatory T cells, as well as various myeloid subsets. Notably, despite identical disease stage and treatment background, the composition of the immune cell populations differed considerably between patients. In addition, while analysis of T cell states showed high variability between patients, clonally expanded T cells predominantly adapted similar cell profiles. More importantly, by comparing the immune cell profiles between responders and non-responders and linking the single cell transcriptome to tumor recognition potential, we are able to identify the transcriptome signatures of T cells that are reactive to tumor and dictate the patient's response to immunotherapy. In summary, our study generated an immune cell atlas of human melanoma, revealed the intra-and inter-patient heterogeneity of tumor immune infiltrates, and identified the transcriptome signature of T cells that are predictive of patient's response to immunotherapy.

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