Single-Cell Profiling Defines Transcriptomic Signatures Specific to Tumor-Reactive versus Virus-Responsive CD4+ T Cells

Author:

Magen, Assaf

Nie, Jia

Ciucci, Thomas

Tamoutounour, Samira

Zhao,Yongmei

Mehta,Monika

Tran,Bao

McGavern, Dorian B

Hannenhalli, Sridhar

Bosselut, Rémy
Author Address

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., Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA., Metaorganism Immunology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA., Advanced Biomedical and Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., NCI CCR Sequencing Facility, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA., Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA. Electronic address: remy.bosselut@nih.gov.,

Abstract:

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. Published by Elsevier Inc.

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