Mechanisms of immune evasion in bladder cancer

Paul L Crispen,Sergei Kusmartsev

doi:10.1007/s00262-019-02443-4

Paul L Crispen, Sergei Kusmartsev

Open Access

https://doi.org/10.1007/s00262-019-02443-4

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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.

Highlights

Bladder cancer is the ninth most common malignancy worldwide and the fifth most common in developed countries
Using an experimental mouse model of bladder cancer, we demonstrated that Gr-1+ myeloid-derived suppressor cells (MDSCs) isolated from the spleen of MBT2-tumor bearing mice or naïve bone marrow are able to differentiate into highly immunosuppressive PD-L1+ macrophages upon contact with bladder cancer cells [32]
IL-6 alone could switch differentiation of dendritic cells (DCs) toward macrophages [82], and activates the transcription factor STAT3 which is required for up-regulation of PD-L1 expression [55]; while high levels of P GE2 inhibit DC differentiation, promotes accumulation of MDSCs and drives the cytokine profile toward the M 2 phenotype in DCs/macrophages and Th2 type in T cells [68]

Summary

Introduction

Bladder cancer is the ninth most common malignancy worldwide and the fifth most common in developed countries. IL-6 alone could switch differentiation of DCs toward macrophages [82], and activates the transcription factor STAT3 which is required for up-regulation of PD-L1 expression [55]; while high levels of P GE2 inhibit DC differentiation, promotes accumulation of MDSCs and drives the cytokine profile toward the M 2 phenotype in DCs/macrophages and Th2 type in T cells [68] These data indicate that enhanced and deregulated P GE2 metabolism in the bladder cancer promotes the formation of immunosuppressive tumor-supporting microenvironment. Culture of bone marrow-derived myeloid cells in P GE2-enriched bladder tumor-conditioned medium markedly inhibited the in vitro generation of mature APCs, while promoting the accumulation of monocytic MDSCs and macrophages Chemokines and their receptors are involved in tumor progression by controlling cancer-related inflammation including the recruitment of immune cells to tumor tissue and lymphoid organs [83, 84]. Deregulated HA metabolism in the tumor microenvironment may contribute to the cancer-related inflammation and immune evasion promoting tumor growth

Conclusion

Findings

Compliance with ethical standards