The impact of antibiotic usage on the efficacy of chemoimmunotherapy is contingent on the source of tumorreactive T cells

Michal P. Kuczma, Zhi-Chun Ding, Tao Li, Tsadik Habtetsion, Tingting Chen, Zhonglin Hao, Locke Johnson Bryan, Nagendra Singh, James N. Kochenderfer, Gang Zhou

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

In recent years the combined use of chemotherapy and immunotherapy, collectively termed chemoimmunotherapy, has emerged as a promising treatment option for patients with cancer. Antibiotics are commonly used to reduce infectionrelated complications in patients undergoing chemotherapy. Intriguingly, accumulating evidence has implicated gut microbiota as a critical determinant of host antitumor immune responses, raising the question as to whether the use of broad-spectrum antibiotics would invariably diminish tumor response to chemoimmunotherapies. We investigated the impact of antibiotics on the therapeutic outcomes of cyclophosphamide (CTX) chemotherapy and adoptive T-cell therapy (ACT) where CTX was used as the host-conditioning regimen in mice. We show that antibiotic prophylaxis dampened the endogenous T cell responses elicited by CTX, and reduced the efficacy of CTX against B-cell lymphoma. In the ACT setting, antibiotics administration impaired the therapeutic effects of adoptively transferred tumorspecific CD4+ T cells in mice with implanted colorectal tumors. In contrast, long-term antibiotic exposure did not affect the efficacy of ACT using CD19-targeting chimeric antigen receptor (CAR) T cells in mice with systemic B-cell lymphoma, although it correlated with prolonged CAR expression and sustained B-cell aplasia. Our study demonstrates that chemoimmunotherapies may have variable reliance on intestinal microbiota for T cell activation and function, and thus have different sensitivities to antibiotic prophylaxis. These findings may have implications for the judicial use of antibiotics in cancer patients receiving chemoimmunotherapies.

Original languageEnglish (US)
Pages (from-to)111931-111942
Number of pages12
JournalOncotarget
Volume8
Issue number67
DOIs
StatePublished - 2017

Keywords

  • Adoptive T-cell therapy
  • Antibiotics
  • Chimeric antigen receptor
  • Cyclophosphamide
  • Intestinal microbiota

ASJC Scopus subject areas

  • Oncology

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