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Aerobic glycolysis enables the effector differentiation potential of stem-like CD4+ T cells to combat cancer

Cellular & Molecular Immunology (2024)Cite this article

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In 1957, Macfarlane Burnet proposed the theory that harnessing the body’s immune system could be an effective method for cancer treatment [1]. Today, T-cell-based immunotherapies have indeed become a vital part of cancer treatment [2]. However, a deeper understanding of antitumor immunity is still necessary to further support these treatments. Notably, CD4+ T cells are central to mediating antitumor immune responses [3,4,5,6], yet the cellular and molecular programs governing CD4+ T-cell antitumor immunity remain unclear. Our recent research revealed that CD4+ T-cell immunity is critically dependent on an intrinsic stem-like program [7]. After antigen priming, naïve CD4+ T cells develop into a TCF1hiLy108hi stem-like cell state. They can then further differentiate into TCF1‒CXCR6+ effector cells after extensive proliferation. Consequently, these stem-like CD4+ T cells serve as precursor cells, continuously replenishing the effector T-cell pool and sustaining the T-cell response [7]. In this study, with a focus on tumor immunity, we sought to answer a crucial question: what defines CD4+ T-cell stemness, and how does it impact the antitumor response? To address this issue, we employed a well-established CD4+ T-cell antitumor model.

To investigate the antitumor functionality of stem-like CD4+ T cells, we sorted Ly108hiCXCR6‒ and Ly108loCXCR6+ Trp1 cells from B16F10 tumor-bearing mice. Notably, Ly108loCXCR6+ Trp1 cells, but not Ly108hiCXCR6‒ Trp1 cells, produced high levels of IFN-γ (Fig. S1E). More importantly, these two populations reliably represented TCF1hi stem-like and TCF1– effector Trp1 cells, respectively (Fig. 1C). The sorted stem-like and effector Trp1 cells were then adoptively retransferred into new B16F10-bearing Rag1‒/‒ mice (Fig. 1D and Fig. S2A). Adoptive transfer of stem-like Trp1 but not effector Trp1 cells eradicated established B16F10 melanomas (Fig. 1E, F). In line with this finding, the retransferred stem-like Ly108hiCXCR6‒ Trp1 cells self-renewed and gave rise to Ly108loCXCR6+ effectors in new hosts, whereas the retransferred effector Trp1 cells largely disappeared at 12 days postcell transfer (Fig. 1G–J). Therefore, CD4+ effector cells do not persist in vivo, whereas stem-like CD4+ cells both self-renew and replenish the effector cell pool to mediate antitumor immunity.

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Fig. 1: Characterizing CD4+ T-cell stemness in adoptive T-cell immunotherapy against melanoma.

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Acknowledgements

This study received support from an internal fund provided by the Houston Methodist Research Institute (to W.C.). The authors would like to thank the Houston Methodist Flow Cytometry Core Facility for providing excellent services.

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Authors and Affiliations

  1. Immunobiology & Transplant Science Center, Department of Surgery, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA

    Dawei Zou, Xiaolong Zhang, Xiang Xiao, Nancy M. Gonzalez, Laurie J. Minze, Xian C. Li & Wenhao Chen

  2. Department of Cardiovascular Science, Houston Methodist Research Institute, Houston, TX, USA

    Shuang Li

  3. Department of Surgery, Weill Cornell Medicine, Cornell University, New York, NY, USA

    Xian C. Li & Wenhao Chen

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  1. Dawei Zou
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  2. Xiaolong Zhang
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Contributions

DZ, XX, XCL and WC designed the study and wrote the manuscript. DZ performed the core experiments and data analysis. XZ, SL, NMG, and LJM supported the experimental work and data analysis. All the authors have read and approved the final manuscript.

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Correspondence to Wenhao Chen.

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The authors declare no competing interests. XCL is an editorial board member of Cellular & Molecular Immunology, but he has not been involved in the peer review or the decision-making of the article.

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Zou, D., Zhang, X., Li, S. et al. Aerobic glycolysis enables the effector differentiation potential of stem-like CD4+ T cells to combat cancer. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01154-w

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