Single-Cell Profiling Defines Transcriptomic Signatures Specific to Tumor-Reactive versus Virus-Responsive CD4+ T Cells
Assaf Magen,
Jia Nie,
Thomas Ciucci,
Samira Tamoutounour,
Yongmei Zhao,
Monika Mehta,
Bao Tran,
Dorian B. McGavern,
Sridhar Hannenhalli,
Rémy Bosselut
Affiliations
Assaf Magen
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA; Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, USA
Jia Nie
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Thomas Ciucci
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Samira Tamoutounour
Metaorganism Immunology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
Yongmei Zhao
Advanced Biomedical and Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Monika Mehta
NCI CCR Sequencing Facility, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Bao Tran
NCI CCR Sequencing Facility, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Dorian B. McGavern
Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Sridhar Hannenhalli
Metaorganism Immunology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
Rémy Bosselut
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA; Corresponding author
Summary: Most current tumor immunotherapy strategies leverage cytotoxic CD8+ T cells. Despite evidence for clinical potential of CD4+ tumor-infiltrating lymphocytes (TILs), their functional diversity limits our ability to harness their activity. Here, we use single-cell mRNA sequencing to analyze the response of tumor-specific CD4+ TILs and draining lymph node (dLN) T cells. Computational approaches to characterize subpopulations identify TIL transcriptomic patterns strikingly distinct from acute and chronic anti-viral responses and dominated by diversity among T-bet-expressing T helper type 1 (Th1)-like cells. In contrast, the dLN response includes T follicular helper (Tfh) cells but lacks Th1 cells. We identify a type I interferon-driven signature in Th1-like TILs and show that it is found in human cancers, in which it is negatively associated with response to checkpoint therapy. Our study provides a proof-of-concept methodology to characterize tumor-specific CD4+ T cell effector programs. Targeting these programs should help improve immunotherapy strategies. : CD4+ T cells contribute to immune responses to tumors, but their functional diversity has hampered their utilization in clinical settings. Magen et al. use single-cell RNA sequencing to dissect the heterogeneity of CD4+ T cell responses to tumor antigens and reveal molecular divergences between anti-tumor and anti-viral responses. Keywords: CD4(+) T cells, Tumor-infiltrating lymphocytes, single-cell RNA-seq, cancer immunotherapy
