High-grade serous carcinoma (HGSC) of the ovary is predominantly diagnosed at late stages and primarily treated with debulking surgery followed by platinum/taxane-based chemotherapy. Although certain patients benefit significantly from currently used chemotherapy, there are patients who either do not respond or have an inadequate duration of response. We previously showed that tumours from chemoresistant patients have an immunosuppressed pre-existing tumour immune microenvironment with decreased expression of Type I Interferon (IFN1) genes. Efficacy of a ‘STimulator of INterferon Genes’ agonist was evaluated in combination with carboplatin chemotherapy and PD-1 immune checkpoint blockade therapy in the ID8-Trp53^−/− immunocompetent murine model of HGSC. Treatment with STING agonist led to decreased ascites accumulation and decreased tumour burden. Survival of mice treated with a combination of carboplatin, STING agonist and anti-PD-1 antibody was the longest. Tumour immune transcriptomic profiling revealed higher IFN response, antigen presentation and MHC II genes in tumours from STING agonist-treated mice compared to vehicle controls. Flow cytometry analysis revealed significantly higher intra-tumoural PD-1⁺ and CD69⁺CD62L⁻, CD8⁺ T cells in STING agonist-treated mice. These findings will enable rational design of clinical trials aimed at combinatorial approaches to improve chemotherapy response and survival in HGSC patients.

One in seven men in North America is expected to be diagnosed with prostate cancer (PCa) during their lifetime (1, 2). While a wide range of treatment options including surgery, radiation, androgen deprivation and chemotherapy have been in practice for the last few decades, there are limited treatment options for metastatic and treatment resistant disease. Immunotherapy targeting T-cell associated immune checkpoints such as CTLA-4, PD-L1, and PD-1 have not yet proven to be efficacious in PCa. Tumor mutational burden, mutations in DNA damage repair genes, immune cell composition and density in combination with their spatial organization, and expression of immune checkpoint proteins are some of the factors influencing the success of immune checkpoint inhibitor therapies. The paucity of these features in PCa potentially makes them unresponsive to contemporary immune checkpoint inhibition. In this review, we highlight the hallmark events in the PCa tumor immune microenvironment and provide insights into the current state of knowledge in this field with a focus on the role of tumor cell intrinsic events that potentially regulate immune related events and determine therapeutic outcomes. We surmise that the cumulative impact of factors such as the pre-treatment immune status, PTEN expression, DNA damage repair gene mutations, and the effects of conventionally used treatments on the anti-tumor immune response should be considered in immunotherapy trial design in PCa.

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.

Background: Urothelial bladder cancer (UBC) is a highly prevalent disease in North America, however its optimal management remains elusive. The contribution of B cell associated responses is poorly understood in bladder cancer. Lymphoid neogenesis is a hallmark of an active immune response at tumor sites that sometimes leads to formation of tertiary lymphoid structures (TLS) that resemble germinal centers formed in secondary lymphoid organs. Objective: This study was conducted with an aim to investigate the presence and characteristics of TLS in UBC with a focus to compare and contrast the TLS formation in treatment naive low grade non-muscle invasive (NMIBC) and muscle invasive bladder cancers (MIBC). Methods: The study cohort consisted of transurethral bladder resection tumour (TURBT) specimens from 28 patients. Sections showing lymphoid aggregates in hematoxylin and eosin (H&E) stained TURBT specimens were further subjected to multi-color immunohistochemistry using immune cell markers specific to CD20 ⁺ B cells, CD3 ⁺ and CD8 ⁺ T cells, PNAd ⁺ high endothelial venules, CD208 ⁺ mature dendritic cells, CD21 ⁺ follicular dendritic cells to confirm the hallmarks of classical germinal centers. Results: Our pilot study investigating the presence of TLS in bladder cancer patients is the first to demonstrate that well-formed TLS are more common in aggressive high grade MIBC tumors compared to low grade NIMBC. Conclusions: These novel findings suggest B cell mediated anti-tumour humoral immune responses in bladder cancer progression.