Background
The influence of gut microbiota on immunotherapeutic cancer treatments is gaining popularity in recent literature. This literature review investigates the role of gut bacteria in anti-CTLA-4 and anti-PD-1 immunotherapy and possible “oncomicrobiotics” that can potentially lead to a more robust response to these treatments. Ideal oncomicrobiotics would help tailor one’s gut microbiota to a desired composition for maximum response to immunotherapy with less adverse effects. Many challenges plague the creation of such oncomicrobiotics, which will be discussed in more detail in later sections.
The commensal relationship between humans and bacteria is very complex and continues to evolve. The majority of microbes that inhabit the human body are bacteria [
1]. The vast majority (99%) of these commensal bacteria are present in the human gastrointestinal (GI) tract, mostly in the distal colon [
2]. The average human colon houses trillions of bacteria [
2,
3]. Collectively the bacteria that inhabit the human body make up what is referred to as the microbiota, and body sites (e.g., gut, skin, oral cavity) have niche-specific microbiota.
Recently much attention has been dedicated to investigating the relationship between humans and the bacteria inhabiting their GI tracts and how these bacteria influence diseases and disease treatments [
1,
2,
4,
5]. The symbiosis between humans and bacteria is a mutualistic relationship [
6]. Gut bacteria breakdown indigestible compounds and occupy niches and space in the human GI tract that may be otherwise filled with more pathogenic bacteria. On the contrary, humans provide a protected environment and abundant nutrients to gut microbes [
7].
There is a significant difference in the composition of GI bacteria between different individuals and many factors influence the composition of one’s gut microbiota [
8]. These factors include but are not limited to: mode of delivery at birth (vaginal versus Cesarean section), ingestion of breast milk versus formula during infancy, diet, medications and exposure to environmental agents [
8]. The variation in the composition of gut bacteria across populations makes it increasingly difficult to determine how these bacteria influence one’s health. In addition, many of these bacteria are unable to be cultured in the laboratory, which poses quite the challenge when studying them [
9].
Symbiosis is the intimate relationship between two organisms living together in close proximity. Symbiosis can occur as commensalism in which one party benefits while the other is unaffected, mutualism in which both parties benefit or parasitism in which one party benefits at the expense of the other [
6]. “Dysbiosis” is the term used to describe an altered host-gut microbiota relationship. Dysbiosis has been linked to many diseases including type 2 diabetes, inflammatory bowel disease, autoimmune diseases and neurological diseases [
10]. Dysbiosis can not only lead to disease, it can also affect treatments for many diseases. Gut microbes have been shown to influence both innate and adaptive immunity in many ways, but the mechanisms underlying the specific processes are less known. The ongoing evolution of the human immune system makes it increasingly difficult to delineate how gut microbes mediate its effects [
10].
Interestingly, the composition of one’s gut bacteria affects the efficacy and toxicity of immunotherapeutic treatments for certain types of cancer. Eighteen percent of cancers worldwide are attributable to infectious agents, including human papillomavirus (HPV) in cervical cancer, hepatitis C virus in hepatocellular carcinoma and
H. pylori in gastric cancers [
2,
11,
12]. Some viruses, such as HPV, can cause cancer via distinct genetic mechanisms while other microbes, like
H. pylori, lead to local inflammation and epithelial disruption [
11,
12]. In the past, much research investigating the role of gut microbes in the development of cancer has focused on colorectal cancer. It is now clear that gut microbiota are able to influence carcinogenesis both locally and systemically [
13].
While antibiotic-treated germ-free mice (GF mice), which lack gut bacteria, seem to show reduced risk for some types of cancer, the presence of specific gut bacteria are required for the efficacy of some immunotherapeutic treatments. This suggests that gut microbes may have anti-tumor effects as well as carcinogenic potential [
2]. Further investigation into how GI bacteria influence cancer treatments will improve the efficacy of these treatments.
Although the composition of one’s gut microbiota may influence chemotherapy, radiation and other cancer treatments, this review will focus on how GI bacteria influence immunotherapy. Immunotherapy is the use of the body’s own immune system to attack tumor cells, mainly via activation of T cells and downstream cytotoxic effects. Many tumor cells are unrecognizable by T cells and/or have the ability to inactivate T cells by various means. This allows tumor cells to go undetected by the immune system and proliferate uncontrollably.
The activation of T cells to target and destroy cells (e.g. tumor cells) requires 2 signals. T cells must first recognize an antigen in the context of a major histocompatibility complex (MHC) molecule on an antigen presenting cell (APC). The second signal relies on the co-stimulation between the B7 surface molecule of the APC and the CD28 surface molecule on the T cell [
14]. To terminate this co-stimulation, T cells express cytotoxic T lymphocyte antigen 4 (CTLA-4) on their surface. CTLA-4 is a co-inhibitory ligand that binds B7 with a higher affinity than CD28 and this interaction inactivates the primed T cell. The CTLA-4 interaction allows termination of the immune response. In addition, T cells express programmed death 1 (PD-1) that binds to PD-L1 or PD-L2 of other cells (e.g. tumor cells) to terminate the T cell response similarly to CTLA-4. PD-L1 is expressed on many types of tumor cells including lung cancer, melanoma, breast cancer, hepatocellular carcinoma, gastric cancer and pancreatic cancer [
15]. During early development, T cells undergo negative selection in the thymus which prevents them from targeting self-antigens. Tumor cells express self-antigens and thus are not adequately targeted for destruction by T cells. Leach et al. demonstrated that blocking the CTLA-4 receptor led to an increased anti-tumor immune response, suggesting that tumor cells are capable of upregulating CTLA-4 in the tumor microenvironment to avoid detection by the immune system [
16].
Antibodies against CTLA-4 and PD-1/PD-L1 have shown to improve overall survival in many patients with different types of cancer including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma and bladder cancer [
15,
17]. The goal of these treatments is to restoret the anti-tumor responses of T cells [
18]. By blocking the inhibitory pathways of T cells, tumor cells are more susceptible to being targeted and destroyed by T cells. These anti-CTLA-4 and anti-PD-1/PD-L1 antibodies are referred to as immune checkpoint blockades (ICBs).
Although ICBs have been shown to improve overall survival in some cancer patients, only certain tumors express PD-L1. These tumors include squamous carcinoma of head and neck, melanoma and various tumors of the brain, thymus, thyroid, esophagus, liver and pancreas [
15]. However, most early research on these treatments has focused on malignant melanoma and only a subset of patients show clinical responses, often with variable responses and sustainability [
19‐
21]. In 2007, Paulos et al. demonstrated that mice treated with antibiotics showed a diminished immune response to melanoma cells due to the abolished interaction of gut microbes with the TLR4 receptor [
21]. These treatments seem to be influenced by gut microbiota although the exact mechanism is still unclear. Even though cancer treatments using these ICBs have shown promise, they often result in immune-related adverse events (IRAEs) which resemble autoimmune diseases due to the breakdown of self-tolerance. While autoimmunity results from the breakdown of self-tolerance, cancer can develop due to increased self-tolerance [
4]. Thus, ICB therapy acts to decrease self-tolerance and may lead IRAEs.
Since ICB therapy is unsuccessful in some patients and commonly leads to IRAEs, treatment must be balanced to provide maximum efficacy while limiting toxicity. Although many factors dictate the efficacy and toxicity of immunotherapy, it is possible that a specific composition of GI bacteria would allow patients to maximally respond to ICB therapy with fewer IRAEs [
22]. The creation of “oncomicrobiotics”, medications that selectively alter one’s GI bacteria, would help tailor the composition of the microbiome to maximally respond to ICB therapy with fewer IRAEs. Oncomicrobiotics are discussed in detail at the end of this review.
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