The impact of antibiotic usage on the efficacy of chemoimmunotherapy is contingent on the source of tumor-reactive T cells
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Michal P. Kuczma1,6, Zhi-Chun Ding1, Tao Li2, Tsadik Habtetsion1, Tingting Chen1, Zhonglin Hao1, Locke Bryan3, Nagendra Singh4, James N. Kochenderfer5 and Gang Zhou1
1Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
2Department of Oncology and Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Province, PR China
3Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
4Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia, USA
5Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, Maryland, USA
6Current/Present address: Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA
Gang Zhou, email: [email protected]
Keywords: antibiotics; intestinal microbiota; cyclophosphamide; chimeric antigen receptor; adoptive T-cell therapy
Received: September 12, 2017 Accepted: November 26, 2017 Published: December 05, 2017
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 infection-related 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 tumor-specific 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.
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