Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients’ smoking status, and the response to immunotherapy.

With the advent of next-generation sequencing approaches, there has been a renaissance in the microbiome field. Microbial taxonomy and function can now be characterized relatively easily and rapidly-no longer mandating complex culturing approaches. With this renaissance, there is now a strong and growing appreciation for the role of the microbiome (referring to microbes and their genomes) in modulating many facets of physiology-including overall immunity. This is particularly true of the gut microbiome, and there is now an evolving body of the literature demonstrating a role for gut microbes in modulating responses to cancer treatment-particularly immunotherapy. Gut microbes can modulate immunity and antitumor responses via a number of different interactions, and these will be discussed herein. Additionally, data regarding the impact of gut microbes on cancer immunotherapy response will be discussed, as will strategies to manipulate the microbiome to enhance therapeutic responses. These efforts to date are not completely optimized; however, there is evidence of efficacy though much additional work is needed in this space. Nonetheless, it is clear that the microbiome plays a central role in health and disease, and strategies to manipulate it in cancer and overall precision health are being explored.

Treatment with molecularly-targeted therapy has revolutionized cancer care, including BRAF/MEKtargeted melanoma therapy. However responses are heterogenous and frequently not long-lasting. Novel strategies to target resistance are needed. We studied a cohort of patients with resectable metastatic melanoma treated with neoadjuvant BRAF/MEK-targeted therapy (n=52) and noted a strong sexual dimorphism in response to treatment, with female patients demonstrating signi cantly higher rates of a major pathologic response (MPR) (p=0.0001). RNA sequencing of tumors demonstrated enrichment of androgen-related genes in those failing to achieve MPR. Pre-clinical studies validated these ndings, with signi cantly increased tumor growth in male vs female mice treated with BRAF/MEK inhibitors (BRAF/MEKi) (p=0.0005). Androgen receptor (AR) expression was upregulated in tumors of BRAF/MEKitreated mice, and modulation of AR signaling via AR-blockade or castration was associated with signi cantly slower tumor growth (p=0.0001 and p=0.00004, respectively). Together, these results have important implications in the context of treatment with BRAF/MEKi-targeted therapy.

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