γδ T Cells Support Antigen-Specific αβ T cell-Mediated Antitumor Responses during BCG Treatment for Bladder Cancer

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

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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 nonconventional 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 nonconventional γδ T cells. Prior work shows that the 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.

Original languageEnglish (US)
Pages (from-to)1491-1503
Number of pages13
JournalCancer Immunology Research
Volume9
Issue number12
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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