Androgen blockade primes NLRP3 in macrophages to induce tumor phagocytosis

Chaudagar, K. K.; Srikrishnan, R.; Mei, S.; Hirz, T.; Hu, Y.-M.; Argulian, A.; Labadie, B.; Desai, K.; Grimaldo, S.; Kahramangil, D.; Nair, R.; D Souza, S.; Zhou, D.; Li, M.; Doughan, F.; Chen, R.; Shafran, J.; Loyd, M.; Xia, Z.; Sykes, D. B.; Moran, A. E.; Patnaik, A.

doi:10.1101/2023.09.15.557996

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bioRxiv · 10.1101/2023.09.15.557996

Androgen blockade primes NLRP3 in macrophages to induce tumor phagocytosis

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Abstract

Immune-based therapies induce durable remissions in subsets of patients across multiple malignancies. However, there is limited efficacy of immunotherapy in metastatic castrate-resistant prostate cancer (mCRPC), manifested by an enrichment of immunosuppressive (M2) tumor- associated macrophages (TAM) in the tumor immune microenvironment (TME). Therefore, therapeutic strategies to overcome TAM-mediated immunosuppression are critically needed in mCRPC. Here we discovered that NLR family pyrin domain containing 3 (NLRP3), an innate immune sensing protein, is highly expressed in TAM from metastatic PC patients treated with standard-of-care androgen deprivation therapy (ADT). Importantly, ex vivo studies revealed that androgen receptor (AR) blockade in TAM upregulates NLRP3 expression, but not inflammasome activity, and concurrent AR blockade/NLRP3 agonist (NLRP3a) treatment promotes cancer cell phagocytosis by immunosuppressive M2 TAM. In contrast, NLRP3a monotherapy was sufficient to enhance phagocytosis of cancer cells in anti-tumor (M1) TAM, which exhibit high de novo NLRP3 expression. Critically, combinatorial treatment with ADT/NLRP3a in a murine model of advanced PC resulted in significant tumor control, with tumor clearance in 55% of mice via TAM phagocytosis. Collectively, our results demonstrate NLRP3 as an AR-regulated "macrophage phagocytic checkpoint", inducibly expressed in TAM by ADT and activated by NLRP3a treatment, the combination resulting in TAM-mediated phagocytosis and tumor control.

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Chaudagar, K. K., Srikrishnan, R., Mei, S., Hirz, T., Hu, Y.-M., Argulian, A., Labadie, B., Desai, K., Grimaldo, S., Kahramangil, D., Nair, R., D Souza, S., Zhou, D., Li, M., Doughan, F., Chen, R., Shafran, J., Loyd, M., Xia, Z., Sykes, D. B., Moran, A. E., Patnaik, A.. 2023-09-17. Androgen blockade primes NLRP3 in macrophages to induce tumor phagocytosis. https://doi.org/10.1101/2023.09.15.557996

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