Obesity modulates the immune macroenvironment associated with breast cancer development

Abstract

Growing evidence demonstrates a strong correlation between obesity and an increased risk of breast cancer, although the mechanisms involved have not been completely elucidated. Some reports have described a crosstalk between adipocytes, cancer cells, and immune cells within the tumor microenvironment, however, it is currently unknown whether obesity can promote tumor growth by inducing systemic alterations of the immune cell homeostasis in peripheral lymphoid organs and adipose tissue. Here, we used the E0771 breast cancer cell line in a mouse model of diet-induced obesity to analyze the immune subpopulations present in the tumors, visceral adipose tissue (VAT), and spleen of lean and obese mice. Our results showed a significant reduction in the frequency of infiltrating CD8+ T cells and a decreased M1/M2 macrophage ratio, indicative of the compromised anti-tumoral immune response reported in obesity. Despite not finding differences in the percentage or numbers of intratumoral Tregs, phenotypic analysis showed that they were enriched in CD39+, PD-1+ and CCR8+ cells, compared to the draining lymph nodes, confirming the highly immunosuppressive profile of infiltrating Tregs reported in established tumors. Analysis of peripheral T lymphocytes showed that tumor development in obese mice was associated to a significant increase in the percentage of peripheral Tregs, which supports the systemic immunosuppressive effect caused by the tumor. Interestingly, evaluation of immune subpopulations in the VAT showed that the characteristic increase in the M1/M2 macrophage ratio reported in obesity, was completely reversed in tumor-bearing mice, resembling the M2-polarized profile found in the microenvironment of the growing tumor. Importantly, VAT Tregs, which are commonly decreased in obese mice, were significantly increased in the presence of breast tumors and displayed significantly higher levels of Foxp3, indicating a regulatory feedback mechanism triggered by tumor growth. Altogether, our results identify a complex reciprocal relationship between adipocytes, immune cells, and the tumor, which may modulate the immune macroenvironment that promotes breast cancer development in obesity.

Diets Differently Regulate Tumorigenesis in Young E0771 Syngeneic Breast Cancer Mouse Model

“…Many studies have shown that obesity induced proinflammatory cytokines promote metastasis in post-menopausal breast cancer [ 47 , 48 ]. Using diet-induced obesity murine models of E0771 breast cancer (aged above 14 weeks old at the time of tumor inoculation), it has been shown that HFD increases the levels of proinflammatory cytokines in the TME, which correlates with increased tumor size and lung metastasis [ 49 , 50 , 51 , 52 ]. However, in our E0771 implanted pubertal breast cancer model, a short-term HFD feeding in fact increased the latency of tumorigenesis compared to RD, which can be attributed to increased proinflammatory cytokines in the TEM in RD-fed mice.…”

Excess body weight significantly affects systemic and tumor inflammatory status and correlates to poor prognosis parameters in patients with breast cancer

“…In contrast, IL-4 polarizes CD4 T cells towards the Th2 pro-tumor pattern ( Ostrand-Rosenberg, 2008 ). Experimental data indicate that the obesogenic environment significantly increases the percentage of intratumoral CD4 + cells and reduces CD8 counting in BC ( Elisia, 2020 ; Núñez-Ruiz A et al.,2022 ). Each increase of 10 units (kg/m2) in BMI in humans results in a 1.6% increase in CD4 + infiltration in the BC tissue ( Asad, Damicis, Heng, 2022 ), but no data about cytokines profile is available in this context.…”

Potential roles of sex-linked differences in obesity and cancer immunotherapy: revisiting the obesity paradox

“…Using a DIO model implementing a HFD Lumeng et al 57 observed that obesity can significantly alter macrophage polarization within AT shifting from an M2 phenotype observed in lean control mice to an M1 https://doi.org/10.1038/s44324-024-00007-4 inflammatory phenotype indicated by increased expression of TNF and iNOS 57 . Although obesity has been associated with an increased M1 presence in AT, studies from DIO models have indicated that within the tumor microenvironment (TME), obesity can promote M2 skewing that adversely impacts immune responses and promotes tumor growth 58,59 . It is still not clear whether metabolic perturbations of obesity are responsible for this skewing, or the meta-inflammatory state associated with obesity.…”