CCR8⁺ regulatory T cell depletion overcomes immune checkpoint blockade resistance in BRCA2-deficient prostate cancer

Rickman, K. A.; Sun, I. Q.; Parameswaran, R.; Zhu, X.; Cai, E. Y.; Rossi, V.; Ziper, N.; Song, H.; Thai, C.; Li, Y.; Diolaiti, M. E.; Huang, F. W.; Vasudevan, H. N.; Ashworth, A.

doi:10.64898/2026.11.11.765808

bioRxiv · 10.64898/2026.11.11.765808

CCR8⁺ regulatory T cell depletion overcomes immune checkpoint blockade resistance in BRCA2-deficient prostate cancer

Rickman, K. A.·Sun, I. Q.·Parameswaran, R.·Zhu, X.·Cai, E. Y.·Rossi, V.·Ziper, N.·Song, H.·Thai, C.·Li, Y.·Diolaiti, M. E.·Huang, F. W.·Vasudevan, H. N.·Ashworth, A.

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Abstract

BRCA2-mutated prostate cancer is an aggressive, genomically unstable subtype, yet how this genomic instability influences tumor immunity remains undefined. We developed an isogenic, immunocompetent model of Brca2-deficient prostate cancer in which BRCA2 loss activated the cGAS/STING pathway and a type I interferon response across multiple cellular compartments, paradoxically leading to an overall immunosuppressed tumor microenvironment. Within this microenvironment, tumor-associated macrophages were interferon-responsive and expressed the CCR8 ligand Ccl8, and there was enrichment of immunosuppressive CCR8 regulatory T cells (Treg). Anti-PD-1 monotherapy was ineffective and instead reinforced this immunosuppressive circuit, leading to expansion of CCR8 Tregs. However, depletion of CCR8 regulatory T cells overcame resistance to checkpoint blockade. Analysis of human BRCA2-mutated prostate cancer showed elevated CCR8 expression, supporting the translational relevance of the CCR8 Treg axis as a potential therapeutic target in a disease largely refractory to immunotherapy.

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Rickman, K. A., Sun, I. Q., Parameswaran, R., Zhu, X., Cai, E. Y., Rossi, V., Ziper, N., Song, H., Thai, C., Li, Y., Diolaiti, M. E., Huang, F. W., Vasudevan, H. N., Ashworth, A.. 2026-11-12. CCR8⁺ regulatory T cell depletion overcomes immune checkpoint blockade resistance in BRCA2-deficient prostate cancer. https://doi.org/10.64898/2026.11.11.765808

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