Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer

Chaudagar, K.; Hieromnimon, H. M.; Khurana, R.; Labadie, B.; Heirz, T.; Mei, S.; Hasan, R.; Shafran, J.; Kelley, A.; Apostolov, E.; Al-Eryani, G.; Harvey, K.; Rameshbabu, S.; Loyd, M.; Bynoe, K.; Drovetsky, C.; Solanki, A.; Markiewicz, E.; Zamora, M.; Fan, X.; Schuerer, S.; Swarbrick, A.; Sykes, D.; Patnaik, A.

doi:10.1101/2022.05.12.490223

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bioRxiv · 10.1101/2022.05.12.490223

Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer

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Abstract

PTEN loss-of-function occurs in approximately 50% of mCRPC patients, and is associated with a poor prognosis, therapeutic outcomes and resistance to immune-checkpoint inhibitors. Recent clinical studies demonstrated that dual PI3K/AKT pathway inhibition and androgen axis blockade led to a modest improvement in progression-free survival of PTEN-deficient mCRPC patients, but the mechanistic basis for this limited efficacy is unknown. To elucidate potential resistance mechanism(s), we performed co-clinical trials in a prostate-specific PTEN/p53-deficient genetically-engineered mouse model, and discovered that the recruitment of PD-1-expressing tumor-associated macrophages (TAM) thwarts the phagocytosis-mediated anti-tumor efficacy of androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki) combination. Strikingly, we observed a TAM-dependent [~]3-fold enhancement in the overall response rate with the addition of PD-1 antibody (aPD-1) to ADT/PI3Ki combination therapy. Mechanistically, decreased lactate production from PI3Ki-treated tumor cells suppressed histone lactylation (H3K18lac) within TAM, resulting in their phagocytic activation, which was augmented by concurrent ADT/aPD-1 treatment. Consistent with our murine observations, single cell RNA-sequencing analysis of human metastatic PC samples revealed a direct correlation between high glycolytic activity and phagocytosis suppression. Critically, feedback activation of Wnt/{beta}-catenin signaling observed in non-responder mice following ADT/PI3Ki/aPD-1 combination treatment, restored lactate-mediated H3K18lac and suppressed phagocytosis within macrophages. Altogether, these data suggest that reversal of lactate and PD-1-mediated TAM immunosuppression by PI3Ki and aPD-1, respectively, controls tumor growth in combination with ADT, and warrants further clinical investigation in PTEN/p53-deficient mCRPC patients. One Sentence SummaryInhibition of tumor-cell intrinsic lactate production suppresses PTEN/p53-deficient prostate cancer growth via macrophage activation/phagocytosis

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Chaudagar, K., Hieromnimon, H. M., Khurana, R., Labadie, B., Heirz, T., Mei, S., Hasan, R., Shafran, J., Kelley, A., Apostolov, E., Al-Eryani, G., Harvey, K., Rameshbabu, S., Loyd, M., Bynoe, K., Drovetsky, C., Solanki, A., Markiewicz, E., Zamora, M., Fan, X., Schuerer, S., Swarbrick, A., Sykes, D., Patnaik, A.. 2022-05-13. Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer. https://doi.org/10.1101/2022.05.12.490223

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