The Obesity Paradox in Cancer, Tumor Immunology, and Immunotherapy: Potential Therapeutic Implications in Triple Negative Breast Cancer

Abstract

Cancer immunotherapy has been heralded as a breakthrough cancer treatment demonstrating tremendous success in improving tumor responses and survival of patients with hematological cancers and solid tumors. This novel promising treatment approach has in particular triggered optimism for triple negative breast cancer (TNBC) treatment, a subtype of breast cancer with distinct clinical features and poor clinical outcome. In early 2019, the FDA granted the first approval of immune checkpoint therapy, targeting PD-L1 (Atezolizumab) in combination with chemotherapy for the treatment of patients with locally advanced or metastatic PD-L1 positive TNBC. The efficacy of immuno-based interventions varies across cancer types and patient cohorts, which is attributed to a variety of lifestyle, clinical, and pathological factors. For instance, obesity has emerged as a risk factor for a dampened anti-tumor immune response and increased risk of immunotherapy-induced immune-related adverse events (irAEs) but has also been linked to improved outcomes with checkpoint blockade. Given the breadth of the rising global obesity epidemic, it is imperative to gain insight into the immunomodulatory effects of obesity in the peripheral circulation and within the tumor microenvironment. In this review, we resolve the impact of obesity on breast tumorigenesis and progression on the one hand, and on the immune contexture on the other hand. Finally, we speculate on the potential implications of obesity on immunotherapy response in breast cancer. This review clearly highlights the need for in vivo obese cancer models and representative clinical cohorts for evaluation of immunotherapy efficacy.

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

“…236 Of special consideration is cytokine release syndrome or "cytokine storm" and immunotherapy-induced immune-related adverse events (irAEs) that may be potentially exacerbated in obesity, reported in one mouse obesity study in tumor-free mice. 229,247 In our hands, however, immunotherapy does not induce cytokine release syndrome in obese mice with tumors (unpublished observations).…”

High dimensional immunotyping of the obese tumor microenvironment reveals model specific adaptation

“…Previous reports have suggested that obese patients tend to have worse responses to traditional cancer therapies but do better with immunotherapy than non-obese patients (Wang et al, 2019). It is not clear why obese patients respond so well to checkpoint blockade immunotherapies but it may be due to the existing immune dysregulation and chronic low-grade inflammation in obese patients (Naik et al, 2019). It has been shown that patients with lower CD8 expression in the tumor microenvironment tend to have worse outcomes in response to traditional therapies (Liu et al, 2012;Mahmoud et al, 2012).…”

The Confounders of Cancer Immunotherapy: Roles of Lifestyle, Metabolic Disorders and Sociological Factors

“…This inflammatory state is known to change the immune landscape by several mechanisms, including a decrease in thymic function, polarization of macrophage to M2 macrophage and prolonged stimulation from toll like receptors (TLRs) expressed by antigen presenting cells. Inevitably, obesity also modulates the tumor response to CPI treatment [ 197 ].…”