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

• Published in: Oncoimmunology Vol. 11; no. 1; p. 2012961
• Main Authors: Li, Shamin, Zhuang, Summer, Heit, Antja, Koo, Si-Lin, Tan, Aaron C., Chow, I-Ting, Kwok, William W., Tan, Iain Beehuat, Tan, Daniel S.W., Simoni, Yannick, Newell, Evan W.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 31.12.2022; Taylor & Francis Group
• Subjects: bystander; cancer; CD39; CD4; CD8; CD8-Positive T-Lymphocytes; HCMV; Humans; infiltrating; Lung Neoplasms; Lymphocytes, Tumor-Infiltrating - pathology; T-Lymphocytes, Regulatory; TIL; tumor; infiltrating; CD4; HCMV; bystander; CD8; TIL; tumor; CD39; cancer
• ISSN: 2162-402X; 2162-4011; 2162-402X
• DOI: 10.1080/2162402X.2021.2012961

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, we reveal that CD4 + TILs are phenotypically heterogeneous, 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 can also recognize cancer-unrelated antigens and suggest measuring CD39 expression as a straightforward way to quantify or isolate bystander CD4 + T cells.