Androgen receptor–positive prostate cancer (PCa) and estrogen receptor–positive luminal breast cancer (BCa) are generally less responsive to immunotherapy compared with certain tumor types such as melanoma. However, the underlying mechanisms are not fully elucidated. In this study, we found that FOXA1 overexpression inversely correlated with interferon (IFN) signature and antigen presentation gene expression in PCa and BCa patients. FOXA1 bound the STAT2 DNA-binding domain and suppressed STAT2 DNA-binding activity, IFN signaling gene expression, and cancer immune response independently of the transactivation activity of FOXA1 and its mutations detected in PCa and BCa. Increased FOXA1 expression promoted cancer immuno- and chemotherapy resistance in mice and PCa and BCa patients. These findings were also validated in bladder cancer expressing high levels of FOXA1. FOXA1 overexpression could be a prognostic factor to predict therapy resistance and a viable target to sensitize luminal PCa, BCa, and bladder cancer to immuno- and chemotherapy.

Purpose: Immunotherapies targeting immune checkpoint molecules have shown promising treatment for a subset of cancers; however, many “cold” tumors, such as prostate cancer, remain unresponsive. We aimed to identify a potential targetable marker relevant to prostate cancer and develop novel immunotherapy.Experimental Design: Analysis of transcriptomic profiles at single-cell resolution was performed in clinical patients' samples, along with integrated analysis of multiple RNA-sequencing datasets. The antitumor activity of YY001, a novel EP4 antagonist, combined with anti–programmed cell death protein 1 (PD-1) antibody was evaluated both in vitro and in vivo.Results: We identified EP4 (PTGER4) as expressed in epithelial cells and various immune cells and involved in modulating the prostate cancer immune microenvironment. YY001, a novel EP4 antagonist, inhibited the differentiation, maturation, and immunosuppressive function of myeloid-derived suppressor cells (MDSC) while enhancing the proliferation and anticancer functions of T cells. Furthermore, it reversed the infiltration levels of MDSCs and T cells in the tumor microenvironment by overturning the chemokine profile of tumor cells in vitro and in vivo. The combined immunotherapy demonstrated a robust antitumor immune response as indicated by the robust accumulation and activation of CD8+ cytotoxic T cells, with a significantly decreased MDSC ratio and reduced MDSC immunosuppression function.Conclusions: Our study identified EP4 as a specific target for prostate cancer immunotherapy and demonstrated that YY001 inhibited the growth of prostate tumors by regulating the immune microenvironment and strongly synergized with anti–PD-1 antibodies to convert completely unresponsive prostate cancers into responsive cancers, resulting in marked tumor regression, long-term survival, and lasting immunologic memory.

Introduction Patients with locally advanced prostate cancer are at high risk of recurrence after definitive treatment. There are emerging data that radical prostatectomy can delay the progression of castration resistance and potentially prolong survival. Neoadjuvant radiation therapy improves local control and has shown survival benefit with favourable toxicity profiles in several other malignancies. We have designed this trial to investigate whether this combination, which theoretically maximises local control, is a safe and feasible approach for treating locally advanced prostate cancer. Methods and analysis This study is a phase I, open-label study to investigate the safety and feasibility of neoadjuvant hormone and radiation therapy followed by robot-assisted radical prostatectomy by a traditional 3+3 dose-escalation design with four planned radiation dose levels (39.6 Gy/22F, 45 Gy/25F, 50.4 Gy/28F and 54 Gy/30F). Locally advanced prostate cancer patients with positive pelvic and/or retroperitoneal lymph nodes will be recruited. The primary objective is to determine the adverse events and maximal tolerable dose (MTD) of neoadjuvant radiotherapy. Toxicity will be assessed using the National Cancer Institute Common Toxicity Criteria V.5.0. Ethics and dissemination This protocol was approved by the Institutional Review Board of Shanghai Changhai Hospital (ref. CHEC2019-070 and CHEC2019-082). The study will be performed in compliance with applicable local legislation and in accordance with the ethical principles developed by the World Medical Association in the Declaration of Helsinki 2013. Study results will be disseminated through conferences and peer-reviewed scientific journals. Trial registration numbers ChiCTR1900022716; ChiCTR1900022754.

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of antibiotic prophylaxis versus no antibiotic prophylaxis in people undergoing transperineal prostate biopsy.