Abstract 3962: A CCR6+Th1-like CD4+T-cell cluster involved in HEV formation predicted lung cancer patients requiring anti-CTLA-4 therapy
Authors: Kagamu Hiroshi , Yamasaki Satoshi , Mouri Atsuhito , Yamaguchi Ou , Shiono Ayako , Nishihara Fuyumi , Miura Yu , Hashimoto Kosuke , Imai Hisao , Kaira Kyoichi , Koabayashi Kunihiko , Horimoto Katsuhisa 
Published: March 2024

Abstract
Background: CD4+ T cells are known to help in cytotoxic T-cell priming, clonal proliferation, migratory and infiltrative capacity, and target cell killing function by licensing dendritic cells. Although CXCR3+ CCR6- classical Th1 CD4+ T cells are thought to be essential for acute cellular immunity, such as antiviral responses, the details of Th1-type CD4+ T cells required for anti-tumor immunity as a long-term chronic T cell immune responses over years remain unclear. We reported the Th7R, a CCR6 expressing Th1-like CD4+ T cell cluster predicted anti-PD-1 antibody therapy efficacy and postoperative recurrence-free survival.
Objective: In this study, we focus on two Th1-like CD4+ T cell clusters, Th1 and Th7R, to determine their functions and roles in long-lasting anti-tumor immune phenomena.
Methods: We studied patients with advanced stage lung cancer treated with immune checkpoint inhibitors (Pembrolizumab monotherapy n=63, Ipilimumab + Nivolumab n=148) and stage I-II lung cancer patients undergoing surgery (n=54). Mass cytometry, single cell RNA sequencing, and immunohistochemical staining were performed using peripheral blood, tumor-infiltrating lymphocytes and lymph node T cells. These studies were approved by the IRB of Saitama Medical University International Medical Center, and all patients gave written consent.
Results: Unlike classical Th1, which highly expresses PRF1, GZMB, GNLY, and NKG7, Th7R expressed LTβ, CXCR6, CTLA-4, CD28, and CXCL13. Analysis of HEV index (MECA79+/CD31+ vessels) by MECA79 and CD31 staining of tumor tissues showed that Th7R in peripheral blood correlated with tumor tissue HEV index, suggesting that LTβ and CXCL13 expressed by Th7R are involved in HEV formation.Th1 mainly expressed PD-1 and did not express CTLA-4, whereas Th7R expressed both PD-1 and CTLA-4. When pre-treatment peripheral Th7R quartile was used to analyze OS after Ipilimumab + Nivolumab treatment, both the top 25% and intermediate 50% patients showed favorable prognosis, but the lower 25% had significantly poor OS. In contrast, only the top 25% Th7R patients but not the intermediate 50% and lower 25% patients who were treated with Pembrolizumab had favorable OS. Thus, it is likely that the Th7R intermediate 50% patients required anti-CTLA-4 therapy to achieve antitumor immune responses. These results may be useful for stratification of patients requiring anti-CTLA-4 antibody therapy as well as for predicting the therapeutic response of Ipilimumab + Nivolumab.
Conclusion: Th7R exhibits LTβ and CXCL13 expression, which is absent in classical Th1, and may help maintain sustained T-cell immunity through HEV/TLS formation. Th7R may be a biomarker to select the patients who benefit from anti-CTLA-4 treatment.
Citation Format: Hiroshi Kagamu, Satoshi Yamasaki, Atsuhito Mouri, Ou Yamaguchi, Ayako Shiono, Fuyumi Nishihara, Yu Miura, Kosuke Hashimoto, Hisao Imai, Kyoichi Kaira, Kunihiko Koabayashi, Katsuhisa Horimoto. A CCR6+Th1-like CD4+T-cell cluster involved in HEV formation predicted lung cancer patients requiring anti-CTLA-4 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3962.