Mechanisms of immune evasion in bladder cancer

Abstract

With the introduction of multiple new agents, the role of immunotherapy is rapidly expanding across all malignancies. Bladder cancer is known to be immunogenic and is responsive to immunotherapy including intravesical BCG and immune checkpoint inhibitors. Multiple trials have addressed the role of checkpoint inhibitors in advanced bladder cancer, including atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab (all targeting the PD1/PD-L1 pathway). While these trials have demonstrated promising results and improvements over existing therapies, less than half of patients with advanced disease demonstrate clinical benefit from checkpoint inhibitor therapy. Recent breakthroughs in cancer biology and immunology have led to an improved understanding of the influence of the tumor microenvironment on the host's immune system. It appears that tumors promote the formation of highly immunosuppressive microenvironments preventing generation of effective anti-tumor immune response through multiple mechanisms. Therefore, reconditioning of the tumor microenvironment and restoration of the competent immune response is essential for achieving optimal efficacy of cancer immunotherapy. In this review, we aim to discuss the major mechanisms of immune evasion in bladder cancer and highlight novel pathways and molecular targets that may help to attenuate tumor-induced immune tolerance, overcome resistance to immunotherapy and improve clinical outcomes.

Keywords: Bladder cancer; Cancer immunotherapy; Immune evasion; Immune tolerance; Tumor microenvironment.

Fig. 1

Tumors recruit immunosuppressive MDSCs and tolerogenic T regs. Malignant cells constantly secrete significant amounts of chemoattractants, such as CCL2, CCL18, and CCL1 that support cancer-related inflammation and stimulate recruitment of MDSCs to the tumor’s vicinity. MDSCs give rise to the development of tDCs and PD-L1⁺ TAMs that migrate through lymphatics to draining lymph nodes and stimulate the generation of T regs. Accumulation of T regs and MDSCs promote immune suppression in the tumor microenvironment

Fig. 2

Bladder tumor-induced immune suppression promotes the escape of malignant epithelial bladder cells from the immune system. Upon entering tumor tissue, the myelomonocytic cells such as MDSCs, depending on local milieu, differentiate into PD-L1⁺ tDCs or PD-L1⁺ TAMs. These PD-L1-expressing APCs are immunosuppressive and capable of induction T cell anergy and/or T cell apoptosis in an antigen-specific manner. Inability of the host’s immune system to generate an effective T cell-mediated anti-tumor immune response results in tumor protection and promotes further tumor growth

Fig. 3

TAMs play multifaceted roles in tumor development and progression. TAMs arise from tumor-recruited blood monocytes or myeloid progenitors including MDSCs. Tumor microenvironment and local cytokine milieu promote polarization of TAMs making them immunosuppressive and tumor-supporting cells. TAMs are abundant in tumor stoma. These cells secrete multiple factors that promote tumor growth via stimulation of tumor angiogenesis, tumor invasion, inflammation and immune escape