The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSCs) as the major infiltrating immune cell type and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified Cxcl5 as a cancer-secreted chemokine to attract Cxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo-YAP signaling in driving Cxcl5 upregulation in cancer cells through YAP-TEAD complex and promoting MDSCs recruitment. Clinico-pathological studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC relevant genes. Together, YAP-driven MDSC recruitment via heterotypic Cxcl5-Cxcr2 signaling reveals effective therapeutic strategy for advanced prostate cancer. Significance We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell non-autonomous function of Hippo-YAP pathway in regulation of Cxcl5, a ligand for Cxcr2 expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CxCl5-Cxcr2 signaling circuit elicits robust anti-tumor responses and prolongs survival.
A significant fraction of advanced prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC)1. Immune checkpoint blockade (ICB) using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types2. However, mCRPC showed overwhelming de novo resistance to ICB3–5, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumor immune evasion6. Circulating MDSC abundance correlates with PSA levels and metastasis in PCa patients7–9. Mouse models of PCa show that MDSCs (CD11b+ Gr1+) promote tumor initiation10 and progression11. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of ICB agents together with targeted agents that neutralize MDSCs yet preserve T cell function. Here we developed a novel chimeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumor activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when ICB was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of IL-1ra and suppression of MDSC-promoting cytokines secreted by PCa cells. These observations illuminate a clinical path hypothesis for combining ICB with MDSC-targeted therapies in the treatment of mCRPC.
Objective Examine whether racial disparities in utilization and outcomes of total knee and total hip arthroplasty (TKA and THA) have declined over time. Methods We used 1991-2008 Medicare Part A (MedPAR) data to identify four separate cohorts of patients (primary TKA, revision TKA, primary THA, revision THA). For each cohort, we calculated standardized arthroplasty utilization rates for White and Black Medicare beneficiaries for each calendar year and examined changes in disparities over time. We examined unadjusted and adjusted arthroplasty outcomes (30-day readmission rate, discharge disposition etc.) for Whites and Blacks and whether disparities decreased over time. Results In 1991 utilization of primary TKA was 36% lower for Blacks compared to Whites (20.6 per 10,000 for Blacks; 32.1 per 10,000 for Whites; p<0.0001); in 2008 utilization of primary TKA for Blacks was 40% lower for Blacks (41.5 per 10,000 for Blacks; 68.8 per 10,000 for Whites; p<0.0001) with similar findings for the other cohorts. Black-White disparities in 30-day hospital readmission increased significantly from 1991-2008 among three patient cohorts. For example in 1991 30-day readmission rates for Blacks receiving primary TKA were 6% higher than for Whites; by 2008 readmission rates for Blacks were 24% higher (p<0.05 for change in disparity). Similarly, Black-White disparities in the proportion of patients discharged-to-home after surgery increased across the study period for all cohorts (p<0.05). Conclusions In an 18-year analysis of Medicare data we found little evidence of declines in racial disparities for joint arthroplasty utilization or outcomes.
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