Bacillus Calmette-Guérin (BCG) is the most effective intravesical agent at reducing recurrence for patients with high-grade, non-muscle invasive bladder cancer. Nevertheless, response to BCG is variable and strategies to boost BCG efficacy have not materialized. Prior work demonstrated a requirement for either conventional αβ or non-conventional γδ T cells in mediating BCG treatment efficacy, yet the importance of T-cell antigen specificity for BCG's treatment effect is unclear. Here, we provide direct evidence to show that BCG increases the number of tumor antigen-specific αβ T cells in patients with bladder cancer and protects mice from subsequent same-tumor challenge, supporting BCG induction of tumor-specific memory and protection. Adoptive T-cell transfers of antigen-specific αβ T cells into immunodeficient mice challenged with syngeneic MB49 bladder tumors showed that both tumor and BCG antigen-specific αβ T cells contributed to BCG efficacy. BCG-specific antitumor immunity, however, also required non-conventional γδ T cells. Prior work shows that mammalian target of rapamycin (mTOR) inhibitor, rapamycin, induces the proliferation and effector function of γδ T cells. Here, rapamycin increased BCG efficacy against both mouse and human bladder cancer in vivo in a γδ T cell-dependent manner. Thus, γδ T cells augment antitumor adaptive immune effects of BCG and support rapamycin as a promising approach to boost BCG efficacy in the treatment of non-muscle invasive bladder cancer.
Cancer immunology research. 2021 Oct 04 [Epub ahead of print]
Niannian Ji, Neelam Mukherjee, Zhen-Ju Shu, Ryan M Reyes, Joshua J Meeks, David J McConkey, Jonathan A Gelfond, Tyler J Curiel, Robert S Svatek
Urology, UT Health at San Antonio., Urology, The University of Texas Health Science Center at San Antonio., Experimental Development Therapeutics Program/Urology, The Cancer Therapy and Research Center/UT Health Science Center., Department of Microbiology, Immunology, and Molecular Genetics, The University of Texas Health Science Center at San Antonio., Department of Urology, Northwestern University Feinberg School of Medic., The Greenberg Bladder Cancer Institute, Johns Hopkins School of Medicine., Epidemiology and Biostatistics, The University of Texas Health Science Center at San Antonio., Department of Medicine, University of Texas Health San Antonio., Urology, UT Health San Antonio .