Deciphering the role of immune system in the obesity–cancer relationship

Obesity and its associated meta-inflammation lead to metabolic and functional reprogramming of immune cells. In a recent Nature paper, Bader et al. show that obesity selectively induced PD-1 expression on tumor-associated macrophages, which triggers a feedback mechanism impairing tumor immune surveillance by notably metabolically reprogramming cytotoxic T cells.

Western lifestyle is characterized by excessive daily caloric consumption coupled with sedentarism for prolonged periods of time.¹ The energy intake of a modern individual often exceeds its consumption, with the energetic surplus being predominantly accumulated in liver and adipose tissues. This imbalance affects the homeostasis in vital metabolic organs and renders an individual susceptible to obesity.² Obesity is the major non-infectious pandemia and even if the disease is rarely fatal in itself, it is clinically associated with a myriad of complications and comorbidities, from an increased sensitivity to pollen to the development of many different types of cancer. Stressed metabolic organs such as liver or adipose tissue from obese individuals activate the immune system, leading to a condition of chronic low-grade inflammation, which paves the way to the development of further pathologies.³ Cancers are a spectrum of diseases for which the causal relationship with chronic inflammation is clearly established with obesity, one of the main risk factors to develop cancer.⁴ Nevertheless, we are still far from precisely understanding these wide clinical observations and further studies have to be conducted to decipher molecular mechanisms underlying this relation.

Bader et al.⁵ have addressed part of this in a recent study, focusing their attention on the receptor PD-1, the immune checkpoint targeted in various immunotherapy protocols.⁶ It has been widely reported that even if obese individuals are more susceptible to develop cancer, they also respond better to anti-PD-1 immunotherapy,⁷ a process which has been referred to as an “obesity paradox”.⁸ Bader and colleagues have confirmed here these clinical observations by injecting the murine cancer cell line MC38 to mice subjected to low fat or high fat diet (HFD) and treated with anti-PD-1 or its isotype control. They have performed scRNA-seq on immune and non-immune cells and observed that not only T cells, but also tumor-associated macrophages (TAMs) were affected by HFD. Then, they confirmed PD-1 expression by TAM at the protein level in mice and human and its increase in response to HFD. The authors highlighted the functional heterogeneity of MC38 TAMs with respect to their PD-1 expression profile. In detail, they sorted PD-1^– and PD-1⁺ TAMs for bulk RNA-seq and observed that PD-1⁺ TAMs had signatures of mitochondrial metabolism, increased mitochondrial mass, elevated lipid uptake and oxidative phosphorylation. In contrast, PD-1^– TAMs had a phagocytic signature. The authors have also used macrophages extracted from Pdcd1^–/– mice (PD1 KO mice) or wild-type littermates treated with anti-PD-1 and confirmed that Pdcd1^–/– macrophages were more prone to glucose uptake, glycolysis and phagocytosis (corroborating the findings of PD-1^– TAMs).

While this piece of evidence introduces PD-1 as a regulator of TAM metabolism, the authors were yet to address the causational link between PD-1 presence and TAM function. In this direction, the last part of the study was dedicated in clarifying how PD-1 targeting on TAMs can influence T cell response to tumors. First, they showed that macrophages treated with inflammatory cytokines known to be elevated in obese patients such as IL-6 or IL-1β exhibited increased expression of PD-1. Then, they showed that the response to anti-PD-1 treatment and the subsequent metabolic rewiring of TAMs was T cell independent. Finally, authors used the MC38 mouse model in the LysM^Cre × Pdcd1^fl/fl genetic background to confirm the myeloid-intrinsic role of PD-1. Tumors from myeloid-restricted PD-1-deficient mice developed more slowly, while their TAMs exhibited increased metabolic activity and an improved ability to activate T cells against tumor.

Altogether, this outstanding study combines state-of-the-art technologies and functional approaches to deliver a clear message: TAMs from obese individuals are metabolically reprogrammed and exhibit notably higher PD-1 expression, which suppresses anti-tumor immunity (Fig. 1). The data reported are well supported and place macrophages at the crossroad between obesity and cancer, highlighting the potential of therapeutic intervention development through manipulations of the PD-1 pathway in TAMs. At the same time, it sheds light on how this widely-used treatment works in tumors, not only reprogramming T cells but also having an impact on TAMs, a feature well apprehended by immunologists but which needs greater echo in the community. Finally, this study pushes the borders of the quite recently founded research field of immunometabolism,⁹ and paves the way for the development of the field of “onco-immunometabolism”, which is promising and should improve our understanding of how metabolic diseases and cancers are linked.

Fig. 1

TAMs from obese individuals express PD-1 and impair anti-tumor immunity.