Strategies for Overcoming Immune Evasion in Bladder Cancer

Abstract

Tumors intricately shape a highly immunosuppressive microenvironment, hampering effective antitumor immune responses through diverse mechanisms. Consequently, achieving optimal efficacy in cancer immunotherapy necessitates the reorganization of the tumor microenvironment and restoration of immune responses. Bladder cancer, ranking as the second most prevalent malignant tumor of the urinary tract, presents a formidable challenge. Immunotherapeutic interventions including intravesical BCG and immune checkpoint inhibitors such as atezolizumab, avelumab, and pembrolizumab have been implemented. However, a substantial unmet need persists as a majority of bladder cancer patients across all stages do not respond adequately to immunotherapy. Bladder cancer establishes a microenvironment that can actively hinder an efficient anti-tumor immune response. A deeper understanding of immune evasion mechanisms in bladder cancer will aid in suppressing recurrence and identifying viable therapeutic targets. This review seeks to elucidate mechanisms of immune evasion specific to bladder cancer and explore novel pathways and molecular targets that might circumvent resistance to immunotherapy.

Keywords: bladder cancer; immune checkpoint inhibitor; immune evasion; immunoregulatory cell; tumor microenvironment.

Figure 1

Bladder cancer evades immune responses by forming an immunosuppressive microenvironment. (A). PD-1 regulates T cell effector functions and acts as a brake on T cell immune responses. HLA-G-induced inhibitory cells have long-term immune regulatory functions, inducing the generation of suppressive cells and blocking immune effector mechanisms. (B). IL-10-positive TAMs showed an immunosuppressive phenotype resembling that of M2 macrophages within the context of MIBC. STn interferes with the expression of MHC-Ⅱ and co-stimulatory molecules in DCs, reducing their ability to display cancer-associated antigens to T cells. (C). PGE2 interferes with anti-tumor immune responses by affecting the function of immune cells such as T cells, DCs, macrophages, and NK cells. (D). Lactate contributes to creating an immunosuppressive TME by reducing the presence of NK cells and cytotoxic T cells, while suppressing the expression of IFN-γ. PD-1, programmed cell death protein 1; HLA-G, human leukocyte antigen G; TAMs, tumor-associated macrophages; MIBC, muscle-invasive bladder cancer; STn, Sialyl Tn; PGE2, prostaglandin E2; DCs, dendritic cells; NK cells, natural killer cells; IFN-γ, interferon- γ.

Figure 2

Potential therapeutic strategies for modulating immune evasion. This diagram summarizes candidate factors for treatment using the various mechanisms that bladder cancer uses to evade immune responses. (Red numbers indicate the sequence of results when the target is blocked, and an x means that the path is suppressed.) Targeting the STn can enhance the expression of MHC class II and costimulatory molecules in DCs and their ability to present antigens to T cells. PD-L1/PD-1 inhibitors can increase the levels of CD4⁺ and CD8⁺ T cells, reduce Tregs, and induce macrophage M1 polarization. Targeting HLA-G can upregulate PD-1 expression on T lymphocytes, block angiogenesis, and activate NK cells. Targeting mPGES1 and employing targeted genetic enhancement of 15-PGDH can reduce PD-L1-mediated immunosuppression. Blocking LDH-A can increase the production of IFN-γ and granzyme B in NK cells and CD8⁺ T cells and enhance anti-tumor immune responses to immune checkpoint inhibitors. Inhibiting CXCL12 produced by CAFs can significantly reduce the effect of CAFs on PD-L1 expression and promote the migration of CD8⁺ T cells toward the tumor stromal area. Targeting the FAM171B protein, which can upregulate CCL2 expression in bladder cancer, can suppress M2 polarization of macrophages and Tregs. STn, Sialyl Tn; DCs, dendritic cells; PD-L1, programmed cell death-ligand 1; PD-1, programmed cell death protein 1; Tregs, regulatory T cells; HLA-G, human leukocyte antigen G; NK cells, natural killer cells; mPGES1, PGE2-producing enzyme microsomal prostaglandin E synthase-1; 15-PGDH, PGE2-degrading enzyme NAD+ dependent 15-hydroxyprostaglandin dehydrogenase; LDH-A, lactate dehydrogenase-A; IFN-γ, interferon-γ; CXCL12, C-X-C motif chemokine 12; CAFs, cancer-associated fibroblasts; CCL2, chemokine(C-C motif) ligand 2; Tregs, regulatory T cells.