The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor?

Abstract

Immune-checkpoint inhibitors (ICI) now represent the standard of care for several cancer types. In pre-clinical models, absence of an intact gut microbiome negatively impacted ICI efficacy and these findings permitted to unravel the importance of the commensal microbiota in immuno-oncology. Recently, multiple clinical studies including more than 1800 patients in aggregate demonstrated the negative predictive impact of treatments with broad-spectrum antibiotics (ATB) on cancer patients receiving ICI. Altogether, these results have led to the hypothesis that ATB-induced dysbiosis might influence the clinical response through the modulation of the gut microbiome. Controversy still remains, as ATB treatment might simply constitute a surrogate marker of unfit or immunodeficient patients. In this review, we summarize recent publications addressing the impact of the gut microbiome on ICI efficacy, discuss currently available data on the effect of ATB administered in different time-frames respect to ICI initiation, and finally, evoke the therapeutic implications of these findings.

Indoxylsulfate, a Metabolite of the Microbiome, Has Cytostatic Effects in Breast Cancer via Activation of AHR and PXR Receptors and Induction of Oxidative Stress

“…Antibiotic use can suppress diversity, and in murine experimental models of breast cancer, the combination of Vancomycin, Neomycin, Metronidazole, Amphotericin, and Ampicillin aggravated the disease [ 25 , 26 ]. This observation is supported by suggestive supportive evidence in human population studies [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Furthermore, probiotic treatment may be protective against the incidence of breast cancer [ 35 , 36 , 37 , 38 ].…”

“…Lower biosynthetic capacity is associated with ER cases [ 40 , 51 ] or triple negative cases [ 9 , 12 , 13 ] that have worse clinical outcomes. In addition, the application of antibiotics, which suppress microbial diversity, increases the risk for breast cancer in human and animal studies [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 82 ]. On the other hand, probiotic treatment, which enriches the gut microbiome, decreases the incidence of breast cancer [ 35 , 36 , 37 , 38 ].…”

“…Currently available data suggest that oncobiosis supports carcinogenesis in breast cancer but has little or no role in initiating oncogenesis. Breast cancer oncobiosis modulates the immune system, including lymphocytes and mast cells [ 16 , 25 , 32 , 39 , 40 , 41 , 42 , 43 ]. Furthermore, oncobiosis supports epithelial-to-mesenchymal transition (EMT) [ 16 , 17 , 40 , 44 ], migration and invasion [ 17 , 40 ], the reduction of oxidative stress [ 40 , 45 ], the proportions of ALDH1+ cancer stem cells [ 17 , 40 ], and widespread metabolic alterations [ 16 , 17 , 40 ] in cancers cells.…”

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

“…Dysbiosis induced by antibiotics was revealed to negatively impact on the clinical outcome of cancer patients who were treated with checkpoint blockade therapies. [234][235][236] Additional factors found to influence susceptibility to irAEs include the patients' genetics/ epigenetics 237 and autoimmunity related to variants in the major histocompatibility complex (MHC) locus. 238 A careful establishment of a risk score specific to each immunotherapy may provide important insights that can be used by clinicians to improve immunotherapeutic strategies while limiting irAEs.…”

Association between the gut microbiota and patient responses to cancer immune checkpoint inhibitors (Review)

“…It has been demonstrated that the use of antibiotics may reduce the benefits of anticancer immunotherapy ( 50 , 51 ). For example, Elkrief et al ( 25 ) studied patients with advanced melanoma who were treated with anti-PD-1 or anti-CTLA-4 monoclonal antibody therapies alone or in combination with chemotherapy and had or had not received antibiotics within 30 days after the start of immunotherapy.…”