PTEN loss-of-function occurs in ~50% of metastatic, castrate-resistant prostate cancer (mCRPC) patients, and associated with poor prognosis and responsiveness to standard-of-care therapies and immune checkpoint inhibitors.
While PTEN loss-of-function hyperactivates PI3K signaling, combinatorial PI3K/AKT pathway and androgen deprivation therapy (ADT) has demonstrated limited anti-cancer efficacy in clinical trials. Here, we aimed to elucidate mechanism(s) of resistance to ADT/PI3K-AKT axis blockade, and to develop rational combinatorial strategies to effectively treat this molecular subset of mCRPC.
Prostate-specific PTEN/p53-deficient genetically engineered mice (GEM) with established 150-200 mm3 tumors, as assessed by ultrasound, were treated with either ADT (degarelix), PI3K inhibitor (copanlisib), or anti-PD-1 antibody (aPD-1), as single agents or their combinations, and tumors were monitored by MRI and harvested for immune, transcriptomic and proteomic profiling, or ex vivo co-culture studies. Single-cell RNAseq on human mCRPC samples was performed using 10X Genomics platform.
Co-clinical trials in PTEN/p53-deficient GEM revealed that recruitment of PD-1-expressing tumor-associated macrophages (TAM) thwarts ADT/PI3Ki combination-induced tumor control. The addition of aPD-1 to ADT/PI3Ki combination led to TAM-dependent ~3-fold increase in anti-cancer responses. Mechanistically, decreased lactate production from PI3Ki-treated tumor cells suppressed histone lactylation within TAM, resulting in their anti-cancer phagocytic activation, which was augmented by ADT/aPD-1 treatment and abrogated by feedback activation of Wnt/β-catenin pathway. Single-cell RNA-sequencing analysis in mCRPC patient biopsy samples revealed a direct correlation between high glycolytic activity and TAM phagocytosis suppression.
Immunometabolic strategies that reverse lactate and PD-1-mediated TAM immunosuppression, in combination with ADT, warrant further investigation in PTEN-deficient mCRPC patients.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 Mar 02 [Epub ahead of print]
Kiranj Chaudagar, Hanna M Hieromnimon, Rimpi Khurana, Brian Labadie, Taghreed Hirz, Shenglin Mei, Raisa Hasan, Jordan Shafran, Anne Kelley, Eva Apostolov, Ghamdan Al-Eryani, Kate Harvey, Srikrishnan Rameshbabu, Mayme Loyd, Kaela Bynoe, Catherine Drovetsky, Ani Solanki, Erica Markiewicz, Marta Zamora, Xiaobing Fan, Stephan Schürer, Alexander Swarbrick, David B Sykes, Akash Patnaik
University of Chicago, Chicago, Illinois, United States., University of Miami Health System, Miami, Fl, United States., Harvard Medical School/ MGH, Boston, United States., Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia., University of Chicago, Chicago, United States., Garvan Institute of Medical Research, Sydney, NSW, Australia., University of Chicago, Chicago, IL, United States., University of Miami Miller School of Medicine, Miami, United States., Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., Massachusetts General Hospital, Boston, MA, United States.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/36862086
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