Obesity‐Associated Myeloid Immunosuppressive Cells, Key Players in Cancer Risk and Response to Immunotherapy

Abstract

Obesity is a risk factor for developing several cancers. The dysfunctional metabolism and chronic activation of inflammatory pathways in obesity create a milieu that supports tumor initiation, progression, and metastasis. Obesity-associated metabolic, endocrine, and inflammatory mediators, besides interacting with cells leading to a malignant transformation, also modify the intrinsic metabolic and functional characteristics of immune myeloid cells. Here, the evidence supporting the hypothesis that obesity metabolically primes and promotes the expansion of myeloid cells with immunosuppressive and pro-oncogenic properties is discussed. In consequence, the accumulation of these cells, such as myeloid-derived suppressor cells and some subtypes of adipose-tissue macrophages, creates a microenvironment conducive to tumor development. In this review, the role of lipids, insulin, and leptin, which are dysregulated in obesity, is emphasized, as well as dietary nutrients in metabolic reprogramming of these myeloid cells. Moreover, emerging evidence indicating that obesity enhances immunotherapy response and hypothesized mechanisms are summarized. Priorities in deeper exploration involving the mechanisms of cross talk between metabolic disorders and myeloid cells related to cancer risk in patients with obesity are highlighted.

Increased inflammatory low-density neutrophils in severe obesity and effect of bariatric surgery: Results from case-control and prospective cohort studies

“…This possibility is important considering that additional signals could derive from infectious agents or malignant cells. It is known that excess weight increases the risk of developing severe infections 18 , 42 and cancer, 43 , 44 suggesting a potential contribution of LDN in developing or exacerbating these co-morbidities.…”

The role of obesity and bariatric surgery-induced weight loss in breast cancer

“…These mechanisms include reduced absolute numbers of activated CD8 + T cells, T cell suppression by PD-1 [241,242], T cell exhaustion [243], and dysfunctional NK cells [244]. Thus, obesity induces a complex and dynamic state of pro-inflammatory immune cell content and function with an influx of monocyte-derived "M1"-like macrophages, combined with reductions in immunomodulatory/ regulatory or dysfunctional immune cells such as regulatory T cells (Tregs), "M2"-like macrophages, or NK Cells, together with an induction of checkpoint ligands (discussed below) [245][246][247][248], and elevated immunosuppressive cells such as immature monocytes or myeloid-derived suppressive cells (MDSCs) [249][250][251][252][253]. Peripheral Treg levels are reduced in correlation with increasing adiposity in humans [254,255].…”

Computational recognition of LncRNA signatures in tumor-associated neutrophils could have implications for immunotherapy and prognostic outcome of non-small cell lung cancer

“…Traditional methods for quantifying tumor immune cells infiltration based on histology or immunohistochemistry may have bias and variabilities (Yoshihara et al, 2013;Gibney et al, 2016;Spranger and Gajewski, 2018;Zhang et al, 2020;Sanchez-Pino et al, 2021). More recently, RNA-seq analyses have shown that lncRNAs exhibit a better degree of cell type specificity, relative to protein-coding genes in immune cells, highlighting their potential as subpopulation-specific immune cells molecular markers (Huang et al, 2018;Chen et al, 2019;Zhou et al, 2021).…”

“…Cytokines and chemokines production by invasive neutrophils might affect the recruitment and activation of inflammatory cells in the TME, create an immunosuppressive microenvironment that is conducive for tumorigenesis, regulate tumor growth, metastasis and angiogenesis, and influence patient prognosis. Traditional methods for quantifying tumor immune cells infiltration based on histology or immunohistochemistry may have bias and variabilities ( Yoshihara et al, 2013 ; Gibney et al, 2016 ; Spranger and Gajewski, 2018 ; Zhang et al, 2020 ; Sanchez-Pino et al, 2021 ). More recently, RNA-seq analyses have shown that lncRNAs exhibit a better degree of cell type specificity, relative to protein-coding genes in immune cells, highlighting their potential as subpopulation-specific immune cells molecular markers ( Huang et al, 2018 ; Chen et al, 2019 ; Zhou et al, 2021 ).…”