The interplay of obesity, gut microbiome and diet in the immune check point inhibitors therapy era
Introduction
Immunotherapy has recently emerged as a promising treatment option for many patients, revolutionizing the established approach in the combat against cancer. The concept of utilizing properties of the immune system against malignancies dates back several decades [1,2]. In the 1890s, Dr. William Coley noticed that cancer patients who suffered from postsurgical infections exhibited better clinical outcomes. Later in the 1950s, Ehrlich proposed that the immune system constantly exerts thorough surveillance on emergent cancer cells that develop several escape mechanisms to survive. These early investigations ignited the field of cancer immunotherapy. Understanding the processes of immune activation, regulation and interplay with malignant cells was necessary before effectively bringing these concepts in clinical practice. T-cell mediated immunity against cancer cells is the central event in cancer immunotherapy, and occurs as an integration of stimulatory, co-stimulatory and inhibitory signals between T-cells and antigen presenting cells (APCs) [2]. Normally, immune checkpoints function as a ‘break’ that regulates inflammatory responses after T-cells are activated. The first immune checkpoint, the Cytotoxic T-lymphocyte associated protein 4 (CTLA-4), was discovered in the 1980’s by Brunet and colleagues, and its role in cancer immune regulation was elucidated by the seminal work of Krumel and Alison [3,4]. Programmed cell death 1 (PD-1), another immune checkpoint receptor of great importance, was discovered in 1992, and after some years, its ligands, PD-L1 and PD-L2 were identified [5]. Many cancers are currently known to take advantage of these immune checkpoints in order to evade immune surveillance. As a result, blockade of the interactions of CTLA-4 as well as PD-1 with their ligands demonstrate potent anti-tumor effects [6].
Monoclonal antibodies inhibiting immune checkpoints (PD-1 and CTLA-4) have demonstrated clinical activity in a wide spectrum of malignances, including melanoma, non-small cell lung cancer (NSCLC), renal cell, bladder and colorectal cancer, head and neck squamous cell carcinoma, Merkel cell carcinoma, and Hodgkin lymphoma. These therapies have collectively revolutionized the practice of medical oncology [1].
However, CTLA-4, PD-1 and PD-L1 inhibitors may lead to non-specific activation of immune pathways [7], enhancing T cell activation and proliferation, and potentially humoral autoimmunity [7]. This can lead in turn, to inflammatory side effects, termed as immune-related adverse events (irAEs), that comprise a major category of ICI complications [8]. IrAEs can affect every organ system. The gastrointestinal tract, skin, endocrine glands, and liver are among the most frequent tissues of irAEs manifestation, with rash, mucositis, diarrhea and colitis being among the most commonly reported. The central nervous system, cardiovascular, musculoskeletal, pulmonary and hematologic systems can also be affected, albeit less frequently [8].
Despite the promising results observed with the use of ICIs in oncology practice, only a minority of patients exhibit durable responses to ICIs with the remaining either failing to respond or eventually progress while on therapy [9]. This heterogeneity of response has been generally attributed to the individualized degrees of immune resistance that can be either tumor intrinsic or host related [10].
In this context, host related parameters, such as body mass index (BMI) and gut microbiome, have recently emerged as strong influences in ICI therapy responsiveness. In the USA, overweight and obesity may cause 14 % of cancer deaths in men and 20 % in women [11]. Obesity not only directly impacts on cancer promotion but also on the immune homeostasis and the elimination, equilibrium, and escape phases of immune-editing [12]. Paradoxically, emerging clinical data have indicated that patients with obesity are benefited from ICI therapy when compared to normal BMI cancer patients [[13], [14], [15], [16], [17]].
It is well established that the gut microbiome in its interaction with the gastrointestinal mucosa, influences local but also systemic immune responses, at the levels of innate and adaptive immunity [18]. Moreover, strong evidence supports the role of the microbiome in cancer therapy, with several recent animal, translational/hybrid and clinical studies demonstrating its influence on the response to ICIs across several cancers [19]. Ongoing clinical trials aim to elucidate how interventions to the microbiome level may be integrated into clinical practice.
The significance of nutrition for cancer prevention and during active treatment and survivorship is well established [20]. Interestingly, nutrition may affect the gut microbiome, which, in turn, exerts potent different effects on immune function [21,22].
The aim of this review is to delineate the associations of ICIs with obesity, host microbiome and nutrition, and to explore how these factors can be effectively leveraged in enhancing the effectiveness of immunotherapy. More specific aims include the determination of how patients with obesity are differentially affected by ICI therapy and potential causes for these observations; how the host microbiome affects response to ICIs; and how the microbiome itself is modulated by obesity and nutrition.
Section snippets
Key molecules and therapeutic targets
The discovery of the two key molecules-immune checkpoints, the CTLA-4 and the Programmed Cell Death receptor systems, has dramatically changed our comprehension of tumor immune resistance and led to the development of multiple novel therapeutics.
The first key molecule, the CTLA-4 is a protein receptor that behaves as an immune checkpoint being expressed on regulatory T-cells (Tregs) [23]. CTLA-4 is a receptor that has been shown to deliver a co-inhibitory signal during early T-cell activation (
What clinical evidence designated the importance of obesity in the ICI efficacy?
Strong evidence from the International Agency for Research on Cancer (IARC) Working Group suggest that cancers of a plethora of anatomic sites, including colorectal, endometrial, ovarian, esophageal and gastric, renal, pancreatic, hepatocellular and postmenopausal breast are directly linked to excess body weight [59]. Several mechanisms have been hypothesized to mediate this association, including chronic low-grade inflammation/compromised immunity; altered adipocytokine secretion;
The human gastro-intestinal ecosystem and its microbiome
The human gut microbiota encompass approximately 1014 bacteria (i.e. 10 times the number of eukaryotic cells in the human body) and millions of associated genes [99]. These bacteria belong to more than 103 different species, representing more than 3 million genes, and corresponding to a biomass weighting approximately 2 kg [100]. The human gut microbiota constitutes an endocrine organ with a multitude of crucial functions in the organism.
This enormous bacterial population colonizes the
Nutrition, microbiome and ICIs
The science of nutrition has been perceived as a potentially key contributor in obtaining, besides prevention, better prognosis and maximal therapeutic response in cancer patients. The central point of counseling for cancer patients has largely been concentrated on cachexia and lack of appetite as a result of advanced disease or therapy side effects, whereas in practice, cancer patients are more likely to have excess weight than a weight deficit [190]. The practice mainstay advices patients to
Conclusion and future perspectives
ICIs have brought about what cancer researchers have fervently been seeking for many years. Some patients with untreatable cancer enjoy lifespans that overpass even the most wishful predictions. Unfortunately, these outcomes are yet to become the norm. Cancer cells, in a complex interplay with their microenvironment, manage to evade the immune system and survive. The ultimate challenge of the immuno-oncology research community is to maximize the efficacy of immunotherapeutics and ICIs in
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