The impact of antibiotic usage on the efficacy of chemoimmunotherapy is contingent on the source of tumor-reactive T cells

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.

Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-α-Dependent Intensification of Oxidative Stress and Tumor Cell Death

“…In recent years, ACT using T cells engineered to express CAR, especially CD19-targeted CAR T cells, has become a viable treatment option for patients with certain types of B cell malignancies (Barrett et al, 2015; Porter et al, 2011; Rosenberg and Restifo, 2015; Sadelain, 2015). Using a retroviral vector carrying a murine CD19-specific CAR design (Kochenderfer et al, 2010), we established a CD19CAR T cell therapy model using A20 B cell lymphoma in immunocompetent mice (Kuczma et al, 2017). As shown in Figure 4E, A20.luci.rCD2 cells were injected to mice via tail vein to establish systemic B cell lymphoma.…”

“…Detailed protocol for T cell viral transduction was previously described (Kuczma et al, 2017). Briefly, T cells were purified from spleens of BALB/c mice on CD45.1 background using the EasySep Mouse T Cell Isolation Kit (STEMCELL Technologies).…”

Cumulative Antibiotic Use Significantly Decreases Efficacy of Checkpoint Inhibitors in Patients with Advanced Cancer

“…In preclinical mouse models, multiple studies have demonstrated that the composition of the gut microbiota is an important factor in tumor immunity and responses to treatment with ICIs. Alteration of the composition of the gut microbiota (either by administrating antibiotics or using germ‐free mice) has been shown to have a negative impact on ICI treatment outcomes . A link between specific gut microbiota, CD4 + regulatory T cells (T reg ), levels of circulating gut‐tropic α4/β7 T cells, and responses to immune checkpoint inhibition with the cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) inhibitor ipilimumab has been established in melanoma .…”

Disruption of the gut microbiota attenuates epithelial ovarian cancer sensitivity to cisplatin therapy

“…In recent years, there has been growing evidence demonstrating a link between the gut microbiome, carcinogenesis and response to cancer therapy (11)(12)(13)(14)(15)(16)(17)(18) to recurrence and survival (17). These findings suggest that certain presence of specific bacterial populations may be essential for treatment response.…”