The ambiguous role of obesity in oncology by promoting cancer but boosting antitumor immunotherapy

Abstract

Obesity is nowadays considered a pandemic which prevalence's has been steadily increasingly in western countries. It is a dynamic, complex, and multifactorial disease which propitiates the development of several metabolic and cardiovascular diseases, as well as cancer. Excessive adipose tissue has been causally related to cancer progression and is a preventable risk factor for overall and cancer-specific survival, associated with poor prognosis in cancer patients. The onset of obesity features a state of chronic low-grade inflammation and secretion of a diversity of adipocyte-derived molecules (adipokines, cytokines, hormones), responsible for altering the metabolic, inflammatory, and immune landscape. The crosstalk between adipocytes and tumor cells fuels the tumor microenvironment with pro-inflammatory factors, promoting tissue injury, mutagenesis, invasion, and metastasis. Although classically established as a risk factor for cancer and treatment toxicity, recent evidence suggests mild obesity is related to better outcomes, with obese cancer patients showing better responses to treatment when compared to lean cancer patients. This phenomenon is termed obesity paradox and has been reported in different types and stages of cancer. The mechanisms underlying this paradoxical relationship between obesity and cancer are still not fully described but point to systemic alterations in metabolic fitness and modulation of the tumor microenvironment by obesity-associated molecules. Obesity impacts the response to cancer treatments, such as chemotherapy and immunotherapy, and has been reported as having a positive association with immune checkpoint therapy. In this review, we discuss obesity's association to inflammation and cancer, also highlighting potential physiological and biological mechanisms underlying this association, hoping to clarify the existence and impact of obesity paradox in cancer development and treatment.

Keywords: Adipose tissue; Cancer; Immunotherapy; Inflammation; Obesity.

Fig. 1

Obesity-related physiological states, immune response and cancer development. Comparison between underweight/lean, overweight/mild obesity and obese phenotypes, regarding their physiological states, immune responses and cancer development. While both extremes—underweight and obese—show poor survival and disadvantages regarding cancer development and progression, mild obesity, in overweight patients, has been described as a protective phenotype, allowing for improved immunotherapy response and survival of cancer patients

Fig. 2

Biological mechanisms of obesity in cancer development and progression. Pathophysiological mechanisms regarding obesity effects upon cancer development and progression. The secretion of adipokines and release of free fatty acids by adipocytes induces several different systemic and cellular responses. The combination of metabolic alterations induced by the adipose tissue results in the activation of several signaling pathways responsible for cellular growth, proliferation, invasion, migration, inhibition of apoptosis, angiogenesis and induction of inflammation, all of which are hallmarks of cancer development

Fig. 3

Implications of obese adipose tissue upon the immune system and immune checkpoint proteins. The dysregulation of the secretion of adipokines, free fatty acids and pro-inflammatory cytokines by the adipose tissue from individuals with obesity has a number of implications upon the immune system. These factors regulate both the proliferation of T cells, as well as their exhaustion, via modulation of PD-1 and PD-L1 expression, also affecting the antitumor immune response against cancer and immune checkpoint inhibitor immunotherapy. The polarization of macrophages from a M2 to a M1 profile induces changes in inflammatory cytokines production, often resulting in a ‘cytokine storm’, an event of uncontrolled inflammation which results in toxicity and failure of different organs