Immune Responses in Bladder Cancer-Role of Immune Cell Populations, Prognostic Factors and Therapeutic Implications

Abstract

Immunosurveillance, which describes the immunologically mediated elimination of transformed cells, has been widely accepted in the context of bladder cancer for many decades with the successful use of Bacillus-Calmette Guerin for superficial bladder cancer since the 1970s. With the emergence of checkpoint inhibitor blockade in the treatment of urothelial cancers, there has been a resurgent interest in the immunology of bladder cancer. The theory of cancer immunoediting proposes that the immune system has both pro-tumorigenic and anti-tumor effects, the balance between the two determining the progression of an individual tumor. However, whilst there is evidence for the action of various immune cell populations in bladder cancer, a cohesive picture of the immune response to bladder cancer and its driving forces are still lacking. Additionally, little is still known about the normal immune landscape of the bladder. Future progress in bladder cancer therapeutic approaches will require a strong foundation in understanding the immunology of this disease. This review considers the evidence for the role of the main immune cell populations, both innate and adaptive, in the immune response to bladder cancer. Recent research and overarching themes in the immune response to bladder cancer are explored. The minimal evidence regarding the normal immune landscape of the human bladder is also summarized to contextualize downstream immune responses. Of specific interest are the innate and myeloid populations, some of which are resident in the human bladder and which have significant effects on downstream adaptive tumor immunity. We discuss factors which restrain the efficacy of populations known to have anti-tumor activity such as cytotoxic T cells, including the constraints on checkpoint blockade. Additionally, the effects on the immune response of tumor intrinsic factors such as the genomic subtype of bladder cancer and the effect of common therapies such as chemotherapy and intravesical Bacillus Calmette-Guerin are considered. A significant theme is the polarization of immune responses within the tumor by a heavily immunosuppressive tumor microenvironment which affects the phenotype of multiple innate and adaptive populations. Throughout, clinical implications are discussed with suggestions for future research directions and therapeutic targeting.

In silico analysis of the immune microenvironment in bladder cancer

“…Pathway analysis revealed enrichment of DEGs in KEGG pathways of cytokine-cytokine receptor interaction, and PI3K/AKT and chemokine signalling. Consistent with these results, previous studies have demonstrated that immune system functions are critical for the formation of a complex BC microenvironment [23,24], which may explain our finding that 97 DEGs were significantly associated with patient survival.…”

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

“…The immune landscape of BlCa is very rich; several immune-cell populations reside in the urinary bladder, and immunotherapies have the advantage of modulating them, namely activating favorable immune populations such as CD8+ T-lymphocytes and Th1 CD4 αβ T-lymphocytes [18]. The immune microenvironment is also linked to the molecular subtypes previously mentioned.…”

Preoperative lymphocyte-to-monocyte ratio improves the prediction of survival outcomes after radical cystectomy for bladder cancer

“…Monocytes play a central role in the production of proinflammatory cytokines, such as monocyte chemoattractant protein-1, that can contribute to cancer initiation and promotion [30]. Additionally, high tumor-associated macrophage (TAM) counts have been found correlated with poor survival and poor response to treatment [31]. However, lymphocytes are essential in antitumor reactions through the induction of tumor cell apoptosis [32] and by mediating antibody-dependent cell-mediated cytotoxicity [33].…”

“…However, lymphocytes are essential in antitumor reactions through the induction of tumor cell apoptosis [32] and by mediating antibody-dependent cell-mediated cytotoxicity [33]. In studies for BCa, the number and function of lymphocyte were both found to be lower in invasive disease than in controls and superficial carcinoma [31,34]. Therefore, a low LMR reflects both a decreased, lymphocyte-mediated, antitumor immune response and a heightened inflammation and immune dysfunction mediated by monocyte [35].…”