The Role of Microbiome in Cancer Immunotherapy The Role of Microbiome in Cancer Immunotherapy
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The Role of Microbiome in Cancer Immunotherapy

Pharma Tech Outlook | Wednesday, February 01, 2023

Microbiomes play an essential role in anticancer immunity, leading to new bacterial-based cancer treatment approaches that enhance tumor immune response.

FREMONT, CA: The human microbiome is acknowledged as a significant contributor to health and disease. Changes in microbiome composition and function have been identified as a unique characteristic of cancer, further corroborating this notion. These effects are exerted via interactions between the microbiome and host cells, influencing various developmental and physiological processes. In this review, we address some of the most recent results on how the bacterial component of the microbiome can affect the efficacy of several cancer immunotherapy modalities, emphasizing the recognized mechanisms of action.

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Immunotherapy for cancer refers to all therapeutic techniques that boost the immune system to attack cancer cells. Immunotherapy development is dominated by immune checkpoint inhibitors (ICIs), which have changed cancer treatment over the past decade. Although ICIs have improved overall survival (OS) in nearly half of the patients, it is still far from ideal in many malignancies. The heterogeneous treatment outcome and development of resistance to ICIs can be attributable to various variables, among which the gut microbiome is hypothesized to play a crucial role. Several studies demonstrate that particular microbiome patterns predict patient response to treatment with antibodies against programmed cell death protein (PD)-1, its ligand PD-L1, and cytotoxic T lymphocyte-associated protein (CTLA)-4 across a variety of solid malignancies. This link was substantiated by observing an increased response to ICI treatment in GF or antibiotic-treated mice after fecal microbiota transplantation (FMT) from ICI-responsive patients. Although these investigations indicated changes in gut microbiome makeup as a complicating factor in response to ICI, there was no consensus regarding the precise microbial signatures linked with the response. Even a meta-analysis of three of these studies failed to produce a common signature, and there needed to be more consistency between the two cohorts of the same study. Despite this evident cohort dependence, our research generated a common signature from our analysis (MELRESIST) and three more studies. Preliminary data reveal that this signature may accurately predict ICI response with 91 percent accuracy across all four investigations; nevertheless, this signature represents the foundation of a medicinal product in development.

Despite discrepancies in reported bacterial signatures, research has been conducted to reveal hypothesized pathways for the effects of particular bacteria in cancer immunotherapy. Among them are the relationships between Akkermansia muciniphila and the clinical response to ICI in patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). By attracting CD4+ T cells into tumor sites, supplementing antibiotic-treated mice receiving FMT from nonresponding patients with this bacterial species overcome ICI resistance. Faecalibacterium and Ruminococcaceae were the most common bacterial taxa in anti-PD-1 antibody-treated melanoma patients who displayed a systemic rise in circulating CD4+ and CD8+ T cell counts. In contrast, a third investigation of stool samples from melanoma patients treated with anti-PD-1/anti-CTLA-4 antibodies revealed that responders had a greater abundance of Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium than nonresponders. These findings of bacterial links to response are consistent with studies indicating a detrimental effect of antibiotic pretreatment on the clinical efficacy of ICI in a variety of cancers, including melanoma, NSCLC, RCC, urothelial carcinoma, and head and neck squamous cell carcinoma, highlighting the significance of microbiome homeostasis in modulating the outcome of ICI therapy.

The microbiome of the gut may potentially influence other cancer immunotherapies. An analysis of a cohort of patients with B cell lymphoma and leukemia indicated a deleterious effect of antibiotic exposure on survival after therapy with anti-CD19 chimeric antigen receptor (CAR) T cells, shown by decreased survival and increased neurotoxicity. In addition, microbiome profiling of B cell lymphoma and leukemia patients undergoing CAR T cell therapy revealed an association between clinical response and specific bacterial taxa, including the genera Ruminococcus and Faecalibacterium, the family Ruminococcaceae, and the species Faecalibacterium prausnitzii and Ruminococcus bromii. Importantly, adoptive T cell treatment (ATC) is another immunotherapy impacted by microbiota alterations. In a mouse model of HPV E6/7-expressing cervical carcinoma TC1, the depletion of Gram-positive bacteria greatly improved the efficiency of ATC, as seen by a reduction in tumor growth relative to controls. This effect was mediated by an upsurge in systemic IL-12-producing CD8+ dendritic cells (DCs) and tumor-infiltrating CD8+ T cells, indicating that alterations in microbiome composition could influence innate immunity and, consequently, antitumor CD8+ T cell responses. In a separate investigation, tumor-resident Bifidobacterium in mice implanted with the MC38 colon adenocarcinoma cell line enhanced the antitumor effects of experimental anti-CD47 antibody immunotherapy. The elimination of anti-CD47 antibody effectiveness confirmed the significance of this tumor-localized commensal upon intratumoral antibiotic injection; these local bacteria improved stimulator of interferon genes (STING) and typed I IFN signaling, resulting in increased cross-priming of DCs. In addition, mice missing DC-specific STING expression did not respond to Bifidobacterium and anti-CD47 antibody therapy, demonstrating the significance of this signaling pathway.

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