Differentiation of stem-like CD4+ T cells modulates early effector responses in colorectal cancer-Shenzhen Bay Laboratory

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Editor's summaryAnti–PD-1 immunotherapies benefit certain patients with mismatch repair–deficient or microsatellite unstable colorectal cancer (CRC), yet mismatch repair–proficient tumors typically show poor responses. Zhang et al. report that responsive high-microsatellite instability tumors feature specific spatial niches containing T helper 1 (TH1)–like cells, immunostimulatory macrophag...

Editor's summary
Anti–PD-1 immunotherapies benefit certain patients with mismatch repair–deficient or microsatellite unstable colorectal cancer (CRC), yet mismatch repair–proficient tumors typically show poor responses. Zhang et al. report that responsive high-microsatellite instability tumors feature specific spatial niches containing T helper 1 (T_H1)–like cells, immunostimulatory macrophages, and CD8⁺ T cells (see the Perspective by Olson). In a CRC model, anti–PD-1 monotherapy initiated a similar intratumoral T_H1 trajectory but did not reduce tumor growth. Conversely, combining anti-OX40 with anti–PD-1 significantly expanded peripheral Il7r⁺ early effector CD4⁺ T cells from stem-like precursors. The combination therapy enhanced migration and transition into intratumoral T_H1-like cells, boosting local and systemic CD8⁺ effector T cell responses and macrophage remodeling. These insights suggest that targeting peripheral CD4⁺ T cell immunity may enhance cancer immunotherapy. —Priscilla N. Kelly

Abstract

Strategies to improve cancer immunotherapy have largely focused on the intratumor immunosuppressive microenvironment, whereas approaches to amplify peripheral T cells and promote tumor recruitment have not been thoroughly explored. Using imaging mass cytometry in patients with colorectal cancer (CRC), we observed T helper 1 (TH1)–like immune architectures in mismatch repair–deficient tumors associated with response to anti–programmed cell death protein 1 (PD-1) immunotherapy. By contrast, mismatch repair–proficient (pMMR) tumors showed regulatory T–dominant spatial interactions. Clonal analyses revealed that stem-like CD4+ T cells differentiated into TH1-like cells after PD-1 blockade. In pMMR CRC mouse models, combined OX40 agonist and PD-1 blockade suppressed tumor progression by expanding Il7r+ early effector CD4+ intermediates in tumor-draining lymph nodes, promoting migration and connection with TH1-like cells. This was accompanied by interferon-γ–dependent induction of immunostimulatory monocyte-macrophages and CD8+ effector T cells. These findings suggest that leveraging peripheral CD4+ T cell amplification may improve immunotherapy responses.

Title

Differentiation of stem-like CD4+ T cells modulates early effector responses in colorectal cancer

Authors

Yu Zhang, Hu Nie, Zixuan Dai, Liying Zhao, Yihong Wan, Yi Wang, Yikang Chen, Xinhua Chen, Zhijun Xu, Jixing Zhong, Dechun Cheng, Qiushuang Wu, Cong Ouyang, Peilu Lin, Haijun Deng, Zhen Liu, Guoxin Li, Chengqian Yin, and Lei Zhang

Journal Information

Science (2026)

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