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bioRxiv · 10.1101/2023.05.15.540889

Interruption of the Intratumor CD8:Treg Crosstalk Improves the Efficacy of PD-1 Immunotherapy

Geels, S. N.·Moshensky, A.·Sousa, R. S.·Walker, B. L.·Singh, R.·Gutierrez, G.·Hwang, M.·Mempel, T. R.·Nie, Q.·Othy, S.·Marangoni, F.
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Abstract

PD-1 blockade unleashes the potent antitumor activity of CD8 cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen response to immunotherapy. Tumor Treg inhibition is a promising strategy to overcome therapeutic resistance; however, the mechanisms supporting tumor Tregs during PD-1 immunotherapy are largely unexplored. Here, we report that PD-1 blockade increases tumor Tregs in mouse models of immunogenic tumors, including melanoma, and metastatic melanoma patients. Unexpectedly, Treg accumulation was not caused by Treg-intrinsic inhibition of PD-1 signaling but instead depended on an indirect effect of activated CD8 cells. CD8 cells colocalized with Tregs within tumors and produced IL-2, especially after PD-1 immunotherapy. IL-2 upregulated the anti-apoptotic protein ICOS on tumor Tregs, causing their accumulation. ICOS signaling inhibition before PD-1 immunotherapy resulted in increased control of immunogenic melanoma. Thus, interrupting the intratumor CD8:Treg crosstalk is a novel strategy that may enhance the efficacy of immunotherapy in patients.

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Geels, S. N., Moshensky, A., Sousa, R. S., Walker, B. L., Singh, R., Gutierrez, G., Hwang, M., Mempel, T. R., Nie, Q., Othy, S., Marangoni, F.. 2023-05-18. Interruption of the Intratumor CD8:Treg Crosstalk Improves the Efficacy of PD-1 Immunotherapy. https://doi.org/10.1101/2023.05.15.540889

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