Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness.

Mutations in PTEN activate the phosphoinositide 3-kinase (PI3K) signalling network, leading to many of the characteristic phenotypic changes of cancer. However, the primary effects of this gene on oncogenesis through control of the PI3K–AKT–mammalian target of rapamycin (mTOR) pathway might not be the only avenue by which PTEN affects tumour progression. PTEN has been shown to regulate the antiviral interferon network and thus alter how cancer cells communicate with and are targeted by immune cells. An active, T cell-infiltrated microenvironment is critical for immunotherapy success, which is also influenced by mutations in DNA damage repair pathways and the overall mutational burden of the tumour. As PTEN has a role in the maintenance of genomic integrity, it is likely that a loss of PTEN affects the immune response at two different levels and might therefore be instrumental in mediating failed responses to immunotherapy. In this review, we summarise findings that demonstrate how the loss of PTEN function elicits specific changes in the immune response in several types of cancer. We also discuss ongoing clinical trials that illustrate the potential utility of PTEN as a predictive biomarker for immune checkpoint blockade therapies.

Background: Accumulating evidence shows that tumor cell-specific genomic changes can influence the cross talk between cancer cells and the surrounding tumor microenvironment (TME). Loss of the PTEN tumor suppressor gene is observed in 20% to 30% of prostate cancers (PCa) when first detected and the rate increases with PCa progression and advanced disease. Recent findings implicate a role for PTEN in cellular type I interferon response and immunosuppression in PCa. However, the way that PTEN inactivation alters antitumor immune response in PCa is poorly understood. Materials and Methods:To investigate the changes associated with PTEN loss and an immunosuppressive TME in PCa, we used CIBERSORT to estimate the relative abundance of 22 immune-cell types from 741 primary and 96 metastatic tumors. Our in silico findings were then validated by immunohistochemical analysis of immune cells and IDO1 and PDL1 checkpoint proteins in a cohort of 94 radical prostatectomy specimens.Results: FoxP3+ T regulatory cells (Tregs) were significantly increased in PTENdeficient PCa in all three public domain cohorts. Loss of PTEN in bone metastases was associated with lower CD8+ T-cell abundance, but in liver metastasis, FoxP3+ Tregs were present at higher levels. PTEN-deficient lymph node metastasis had a distinct profile, with high levels of CD8+ T cells. Moreover, we found that metastatic PCa presents higher abundance of FoxP3+ Treg when compared to primary lesions. Since PTEN-deficient tumors are likely to be immunosuppressed as a consequence of increased FoxP3+ Tregs, we then evaluated the localization and expression of IDO1, PDL1 immune checkpoints, and the corresponding density of FoxP3+ Treg and CD8+ T cells using our validation cohort (n = 94). We found that IDO1 protein expression and FoxP3+ Treg density were higher in neoplastic glands compared with benign adjacent tissue. Moreover, higher densities of FoxP3+ Treg cells in both stromal The Prostate. 2019;79:969-979.wileyonlinelibrary.com/journal/pros

Background Molecular subtyping of urothelial cancer (UC) has significantly advanced the understanding of bladder tumor heterogeneity and development of prognostic and predictive biomarkers. Evolving evidence across cancers strongly suggests that tumor immunoediting has a profound impact on the behaviour of cancer cells and their adaptation to the co-evolving microenvironment and response to treatment. In alignment with these concepts, recent immune checkpoint blockade (ICB) therapies in UC have demonstrated the predictive potential of mutations in the DNA damage repair (DDR) genes. A comprehensive understanding of DDR gene inactivation associated expression of immune regulatory genes could thus aid in expansion of current immunotherapies and predictive biomarkers for the design of patient-tailored combination treatments. Methods We investigated pre-treatment tumor transcriptomic profiles of the five recently described molecular subtypes of muscle invasive urothelial cancer (MIUC; n = 408) from The Cancer Genome Atlas, to determine subtype specific immune cell abundance, expression of 67 immune regulatory genes, and association with DDR gene inactivation (via mutation, copy number alteration) profiles. Results Analysis using CIBERSORT immune cell abundance determination tool showed significant differences in immune cell profiles and abundance between MIUC subtypes. Expression patterns of a selected panel of 67 genes including both immune stimulatory and inhibitory genes, showed significant associations with subtypes, and DDR gene mutation status. Conclusion Findings from our study provide compelling evidence for co-expression of multiple immune checkpoint genes including, PD-1 , PD-L1, IDO1, TIGIT, TIM-3, TGFB1, LAG3, and others, that potentially contribute to compensatory immune evasion in bladder tumors. Our findings also emphasize the urgent need for biomarker discovery approaches that combine molecular subtype, DDR gene mutation status, tumor immune landscape classification, and immune checkpoint gene expression to increase the number of patients responding to immunotherapies. Electronic supplementary material The online version of this article (10.1186/s40425-019-0619-8) contains supplementary material, which is available to authorized users.