Abrogation of HnRNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8+ T cell-mediated ferroptosis in castration-resistant prostate cancer

Owing to incurable castration-resistant prostate cancer (CRPC) ultimately developing after treating with androgen deprivation therapy (ADT), it is vital to devise new therapeutic strategies to treat CRPC. Treatments that target programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for human cancers with clinical benefit. However, many patients, especially prostate cancer, fail to respond to anti-PD-1/PD-L1 treatment, so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy. In the present study, analyzing the data from our prostate cancer tissue microarray, we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L (HnRNP L). Hence, we further investigated the potential role of HnRNP L on the PD-L1 expression, the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC. Indeed, HnRNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo, on the contrary, HnRNP L overexpression led to the opposite effect in CRPC cells. In addition, consistent with the previous study, we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death, and HnRNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells. Furthermore, HnRNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8+ T cells and synergized with anti-PD-1 therapy in CRPC tumors. This study provided biological evidence that HnRNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.

Prostate Cancer and Androgen Deprivation Therapy: Metabolic, Cardiovascular and Psychological Side Effects.

Exposure to androgen deprivation therapy (ADT) by prostate cancer (PCa) patients is increasing, either in early-stage and in metastatic disease. Frequently, ADT becomes a long-term treatment, lasting even more than 10 years, starting with gonadotropin releasing hormone (GnRH) agonists or antagonists, until the newest hormonal treatments as Abiraterone and Enzalutamide. As a consequence, ADT related adverse events occurred. We reviewed the medical literature using Pubmed search terms “prostate cancer”, “androgen deprivation”, “metabolic syndrome”, “cardiovascular diseases” and “psychological assessment”. The search was limited to manuscripts published in English language between 1999 and 2016, preferring more recent review articles. Metabolic syndrome, diabetes and cardiovascular diseases, rather than PCa itself, are the most common causes of mortality, particularly in early stage PCa patients. All these adverse eff ects synergistically increase morbidity in patients taking ADT. Psychological-cognitive implications emerging during ADT result in a signifi cant reduction of health-related quality of life of PCa patients. ADT is associated with several adverse events, which physicians andpatients should evaluate when recommending ADT. Multidisciplinary approach, with diff erent clinicians such as Urologist, Radiotherapist, Oncologist, Endocrinologist, Cardiologist, Psychologist, is mandatory for the suitable clinical management of patients with PCa submitted to ADT.