How can our microbiome help cancer immunotherapy strategies?

The American Cancer society defines immunotherapy as a treatment that uses a person’s own immune system to fight cancer, either boosting or changing how the immune system works so it can target and eliminate cancer cells. In recent years a wide variety of immunotherapies has been developed, such as those based on monoclonal antibodies, chimeric antigen receptor (CAR) T cells, immune checkpoint inhibitors, cancer vaccines, cytokines and immunomodulators. Today we will focus on immune checkpoint inhibitors (ICIs) and how the gut microbiota can influence the success of this kind of therapies. 

One of the most important function of the immune system comprise the ability to discern between normal body cells, foreign organisms, and body cells that became malignant. This allows the immune system to attack pathogens or tumour cells while leaving the healthy body cells alone. To discern the proper target, the immune system uses checkpoints, which are molecules or certain immune cells that need to be activated or inactivated to start an immune response. Immune checkpoints consist of costimulatory and inhibitory receptors with vital functions in maintaining immune system homeostasis and avoiding autoimmunity [1]. Cancerous cells scape from immunity by disturbing the immune checkpoint functions [2], and drugs that target these checkpoints hold a lot of promise as cancer treatments.

Fig 1. PD-1/PD-L1 immune system checkpoint. 

Obtained from Cancers.

ICIs that target cytotoxic T-lymphocyte antigen 4  (CTLA-4) and programmed cell death 1 and its ligand (PD-1/PD-L1)   have ushered in a new era of cancer treatment. CTLA-4 and PD-1 are checkpoint proteins present on immune cells that normally acts as an ‘off switch’ that helps keep the T cells from attacking other cells in the body. When PD-1 binds to PD-L1 it basically tells the T cell to leave the other cell alone; therefore, some cancer cells expresses large amounts of PD-L1, which helps them hide from an immune system attack [3]. ICIs are promising in cancer treatment but have some side effects such as diarrhea, pneumonitis, rashes and itchiness, kidney infections and last but more importantly, a significant proportion of patients demonstrates primary or acquired resistance to ICIs. It is estimated that less than 30% of cancer patients respond to ICIs due to primary or acquired resistance [4]. 

Resistance is ascribed to 1) tumour-intrinsic factors which determine the priming of T cells towards the tumor microenvironment, such as low mutational landscape, mutations in the interferon signaling or antigen-presenting pathways, or oncogenic signaling pathways relevant to immune scape; and 2) host related or environmental factors such as age, diet, hormones, human leukocyte antigen type, genetic polymorphisms, smoking and other secondary ongoing infections [5]. Strategies combining ICIs with radiation, cytotoxicity and other agents to enhance immunogenicity of tumour cells or recruitment of immune cells to cancer sites has been used to overcome primary resistance. 

Recently, gathered evidence highlighted that the diversity and composition of gut microbiota impacts ICIs response or resistance in melanoma, non-small cell lung cancer, urothelial cancer and renal cancer [6-9]. These findings inspired scientists and clinicians to explore whether microbes could be used as biomarkers and therapeutic intervention strategies for ICIs.

Proposed mechanisms of gut microbiota to overcome resistance to ICIs

In 2015 it was proposed the key role of Bacteroides and Bifidobacterium species in the immunostimulatory effects of CTLA-4 and PD-L1 blockade in mice [10, 11]. In 2018 it was confirmed the pivotal role of the gut microbiota in the clinical efficacy of PD-1 inhibitors in melanoma, non-small cell lung cancer, urothelial cancer and renal cancer patients through larger cohorts [6, 8, 9]. Collectively, gut microbiota may be a biomarker or target to predict the efficacy of immune checkpoint therapy. 

Fig 2. Potential mechanisms of gut microbiota to overcome resistance to ICIs.

Obtained from Current Opinion in Pharmacology.

The exact mechanism has not been fully elucidated, but a recent article in Current Opinion in Pharmacology proposed that gut microbes may restore ICIs response via 1) educating local and systemic immune responses; 2) enhancing beneficial effects of the host by metabolites; or 3) alleviating immune-related side effects such as diarrhea and colitis [12]. 

- Education of local and systemic immune response: Dendritic cells are key orchestrators between gut microbiota and antitumor immunity of ICIs. Pathogen-associated molecular patterns (PAMPs) from microbes are recognized by Toll-like receptors (TLRs) present in dendritic cells. Upon recognition, dendritic cells activate the innate immune response to maintain gut homeostasis. Activated dendritic cells can also translocate to the mesenteric lymph nodes to prime the adaptive immune response, which can disseminate systemically and suppress tumor cells.

- Modulation of the immune system through microbial metabolites: Short chain fatty acids (SCFAs) derived from dietary fiber fermentation by the gut microbes serve as the main energy source for intestinal epithelial cells to maintain gut integrity. SCFAs are absorbed across the intestinal epithelium and transmitted to T cells and tumour cells where they inhibit histone deacetylases to suppress their differentiation. Detailed function of SCFAs may depend on the exposure and host-specific factors but it has been described that in the circulation system, SCFAs directly interact with CD8+ T cells and enhance their antitumor effect. 

- Alleviate immune-related side effects: ICIs enhance antitumor immunity while activating autoreactive T cells, damaging host tissues and causing immune-related adverse events. The most common side-effect is ICI-related colitis. Manipulating gut microbiota can significantly and rapidly improve ICI-associated colitis. Bacteroides and Bifidobacterium species has been shown to protect against intestinal damage and colitis in melanoma patients who received CTLA-4 blockade [13, 14]. 

The interactions between gut microbiota, cancer and the immune system are extremely sophisticated, and manipulating gut microbiome is emerging as a new target or potential biomarker in cancer immunotherapy. Consumption of a high-fiber diet appears to lead to more diversity in the gut microbiome and, in turn, to a better response to treatments with ICIs. However, the precise mechanisms that linked gut microbiota to the cancer immunotherapy resistance remains to be elucidated. A multidisciplinary approach should be used to validate this relationship, and more therapeutic intervention strategies should be focused on the modulation of gut microbiota.

References

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