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.