Heterogeneity and origins of CD4+ T cell response in NSCLC
Tumor-draining lymph nodes are important sites for the priming of immune responses, yet their role in the orchestration of the anti-tumor CD4+ T cell response remains under explored. Here, we present an integrative single cell analysis of transcriptome, T cell receptor (TCR), and chromatin accessibility profiles of CD4+ conventional (Tconv) and regulatory (Treg) T cells from matched blood, lymph nodes and tumors of treatment naïve Non-Small Cell Lung Cancer (NSCLC) patients. Among multiple Tconv and Treg subpopulations, we identify a subgroup that are enriched and clonally expanded in tumors and show expression signatures suggesting tumor-specificity of the cognate antigens. Using the TCR as a lineage barcode, we map Treg and Tconv state transitions and migration between tissues and show that precursors for the candidate tumor-specific clones are present in the lymph nodes. Overall, our combined multiomics analysis of cancer patient samples revealed the transcriptional program underlying the differentiation of tumor enriched Treg and Tconv populations, which could guide the design of novel immune modulatory therapies.