Takei et al. identified IL-7Rhi CCR6+ Th1-like CD4+ T cells (Th7R) that were distinct from Th1 and Th17 states. Th7R cells expressed CXCL13 and lymphotoxin-β, localized to TLSs, and associated with high endothelial venules. Th7R abundance correlated with GZMK+GZMB- progenitor exhausted CD8+ T cells (Tpex) across tumors and lymph nodes. Adoptive transfer of Th7R cells into mice bearing MCA205 skin tumors expanded Tpex and Tex populations, supported Tpex maintenance and differentiation, and enhanced tumor control. Intratumoral and circulating Th7R correlated with response to PD-1 blockade, and improved clinical outcomes in patients with lung cancer.
Contributed by Shishir Pant
ABSTRACT: CD4⁺ T cells support the priming, expansion, and function of CD8⁺ T cells through dendritic cells. Precursor exhausted T cells (Tpex) maintain self-renewal and supply cytotoxic CD8⁺ T cells in the tumor microenvironment (TME), but the identity of their CD4⁺ T-cell partners remains unclear. Here, we perform scRNA-seq, scTCR-seq, and mass cytometry analysis on peripheral blood, tumor, and lymph nodes primarily from lung cancer patients and, in part, renal cell carcinoma. We identify an IL-7Rhigh CCR6⁺ Th1-like CD4⁺ T cell-population, named Th7R, that is numerically and spatially partnered with Tpex. Th7R cells express lymphotoxin-β and CXCL13, correlate with high endothelial venules, and co-localize with Tpex in tertiary lymphoid structures. Th7R cell abundance correlates with Tpex numbers in the TME and lymph nodes, and adoptive transfer of Th7R increases Tpex in a preclinical mouse model. Intratumoral Th7R and Tpex associate with improved response to neoadjuvant PD-1 blockade therapy. These results suggest that Th7R cells act as partners of Tpex to sustain antitumor T-cell immunity.
Author Info: (1) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. Department of Respiratory Medicine, Kyoto Pr
Author Info: (1) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. Department of Respiratory Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan. (2) Department of Clinical Cancer Genomics, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (3) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (4) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (5) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (6) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (7) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (8) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (9) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (10) Department of General Thoracic Surgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (11) Department of General Thoracic Surgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (12) Department of General Thoracic Surgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (13) Department of General Thoracic Surgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (14) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (15) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. kagamu19@saitama-med.ac.jp.
