Bystander CD4+ T cells infiltrate human tumors and are phenotypically distinct

Tumor-specific T cells likely underpin effective immune checkpoint-blockade therapies. Yet, most studies focus on Treg cells and CD8+ tumor-infiltrating lymphocytes (TILs). Here we study CD4+ TILs in human lung and colorectal cancers and observe that non-Treg CD4+ TILs average more than 70% of total...

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Published inbioRxiv
Main Authors Simoni, Yannick, Li, Shamin, Zhuang, Summer, Heit, Antja, Si-Lin, Koo, I-Ting, Chow, Kwok, William W, Tan, Iain Beehuat, Tan, Daniel Sw, Newell, Evan W
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 16.07.2020
Subjects
Advisors
Antigens
Cancer
CD4 antigen
CD8 antigen
CTLA-4 protein
Cytometry
Epitopes
Immune checkpoint
Lymphocytes
Lymphocytes T
Neogene
PD-1 protein
Tumor-infiltrating lymphocytes
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Summary:Tumor-specific T cells likely underpin effective immune checkpoint-blockade therapies. Yet, most studies focus on Treg cells and CD8+ tumor-infiltrating lymphocytes (TILs). Here we study CD4+ TILs in human lung and colorectal cancers and observe that non-Treg CD4+ TILs average more than 70% of total CD4+ TILs in both cancer types. Leveraging high dimensional analyses including mass cytometry and single-cell sequencing, we reveal that CD4+ TILs are heterogeneous at both gene and protein levels, within each tumor and across patients. Consistently, we find different subsets of CD4+ TILs showing characteristics of effectors, tissue resident memory (Trm) or exhausted cells (expressing PD-1, CTLA-4 and CD39). In both cancer types, the frequencies of CD39- non-Treg CD4+ TILs strongly correlate with frequencies of CD39- CD8+ TILs, which we and others have previously shown to be enriched for cells specific for cancer-unrelated antigens (bystanders). Ex-vivo, we demonstrate that CD39- CD4+ TILs can be specific for cancer unrelated antigens, such as HCMV epitopes. Overall, our findings highlight that CD4+ TILs cells are not necessarily tumor-specific and suggest measuring CD39 expression as a straightforward way to quantify or isolate bystander CD4+ T cells. Competing Interest Statement Evan William Newell is a co-founder, advisor, and shareholder of ImmunoScape Pte. Ltd. and an advisor for Neogene Therapeutics and Nanostring Technologies.
DOI:10.1101/2020.07.15.204172