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. Kuczma 1, 6 , Zhi-Chun Ding 1 , Tao Li 2 , Tsadik Habtetsion 1 , Tingting Chen 1 , Zhonglin Hao 1 , Locke Bryan 3 , Nagendra Singh 4 , James N. Kochenderfer 5 and Gang Zhou 1 1 Georgia Cancer Center, Augusta University, Augusta, Georgia, USA 2 Department of Oncology and Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Province, PR China 3 Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, Georgia, USA 4 Department of Biochemistry and Molecular Biology, Augusta University, Augusta, Georgia, USA 5 Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, Maryland, USA 6 Current/Present address: Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA Correspondence to: Gang Zhou, email: GZHOU@augusta.edu Keywords: antibiotics; intestinal microbiota; cyclophosphamide; chimeric antigen receptor; adoptive T-cell therapy Received: September 12, 2017      Accepted: November 26, 2017      Published: December 05, 2017 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 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.