Search

Purpose: Repeated instillations of bacillus Calmette et Guérin (BCG) are the gold standard immunotherapeutic treatment for reducing recurrence for patients with high-grade papillary non-muscle invasive bladder cancer (NMIBC) and for eradicating bladder carcinoma-in situ. Unfortunately, some patients are unable to tolerate BCG due to treatment-associated toxicity and bladder removal is sometimes performed for BCG-intolerance. Prior studies suggest that selectively delipidated BCG (dBCG) improves tolerability of intrapulmonary delivery reducing tissue damage and increasing efficacy in preventing Mycobacterium tuberculosis infection in mice. To address the lack of treatment options for NMIBC with BCG-intolerance, we examined if selective delipidation would compromise BCG's antitumor efficacy and at the same time increase tolerability to the treatment. Materials and methods: Murine syngeneic MB49 bladder cancer models and in vitro human innate effector cell cytotoxicity assays were used to evaluate efficacy and immune impact of selective delipidation in Tokyo and TICE BCG strains. Results: Both dBCG-Tokyo and dBCG-TICE effectively treated subcutaneous MB49 tumors in mice and enhanced tumor-infiltrating CD8+ T and natural killer cells, similar to conventional BCG. However, when compared to conventional BCG, only dBCG-Tokyo retained a significant effect on intratumoral tumor-specific CD8+ and γδ T cells by increasing their frequencies in tumor tissue and their production of antitumoral function-related cytokines, i.e., IFN-γ and granzyme B. Further, dBCG-Tokyo but not dBCG-TICE enhanced the function and cytotoxicity of innate effector cells against human bladder cancer T24 in vitro. Conclusions: These data support clinical investigation of dBCG-Tokyo as a treatment for patients with BCG-intolerant NMIBC. [ABSTRACT FROM AUTHOR]

Purpose: Human innate lymphoid cells (hILCs) are lineage‐negative immune cells that do not express rearranged adaptive antigen receptors. Natural killer (NK) cells are hILCs that contribute to cancer defense. The role of non‐NK hILCs in cancer is unclear. Our study aimed to characterize non‐NK hILCs in bladder cancer. Experimental design: Mass cytometry was used to characterize intratumoral non‐NK hILCs based on 35 parameters, including receptors, cytokines, and transcription factors from 21 muscle‐invasive bladder tumors. Model‐based clustering was performed on t‐distributed stochastic neighbor embedding (t‐SNE) coordinates of hILCs, and the association of hILCs with tumor stage was analyzed. Results: Most frequent among intratumoral non‐NK hILCs were hILC1s, which were increased in higher compared with lower stage tumors. Intratumoral hILC1s were marked by Th17‐like phenotype with high RORγt, IL‐17, and IL‐22 compared to Th1 differentiation markers, including Tbet, perforin, and IFN‐γ. Compared with intratumoral hILC2s and hILC3s, hILC1s also had lower expression of activation markers (NKp30, NKp46, and CD69) and increased expression of exhaustion molecules (PD‐1 and Tim3). Unsupervised clustering identified nine clusters of bladder hILCs, which were not defined by the primary hILC subtypes 1–3. hILC1s featured in all the nine clusters indicating that intratumoral hILC1s displayed the highest phenotypic heterogeneity among all hILCs. Conclusions: hILC1s are increased in higher stage tumors among patients with muscle‐invasive bladder cancer. These intratumoral hILC1s exhibit an exhausted phenotype and Th17‐like differentiation, identifying them as potential targets for immunotherapy. [ABSTRACT FROM AUTHOR]