ABSTRACT
Obesity is one of the leading preventable causes of cancer; however, little is known about the effects of obesity on anti-tumor immunity. Here, we investigated the effects of obesity on CD8 T cells in mouse models and patients with endometrial cancer. Our findings revealed that CD8 T cell infiltration is suppressed in obesity, which was associated with a decrease in chemokine production. Tumor-resident CD8 T cells were also functionally suppressed in obese mice, which was associated with a suppression of amino acid metabolism. Similarly, we found that a high BMI negatively correlated with CD8 infiltration in human endometrial cancer and that weight loss was associated with a complete pathological response in six of nine patients. Moreover, immunotherapy using anti-PD-1 led to tumor rejection in lean and obese mice and partially restored CD8 metabolism and anti-tumor immunity. These findings highlight the suppressive effects of obesity on CD8 T cell anti-tumor immunity, which can partially be reversed by weight loss and/or immunotherapy.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Neoplasms/etiology , Neoplasms/metabolism , Obesity/metabolism , Tumor Microenvironment/immunology , Amino Acids/metabolism , Animals , CD8-Positive T-Lymphocytes/metabolism , Diet, High-Fat , Disease Models, Animal , Immunotherapy , Lymphocyte Count , Lymphocytes, Tumor-Infiltrating/metabolism , Mice , Mice, Obese , Neoplasms/pathology , Neoplasms/therapy , Obesity/etiologyABSTRACT
Annexin 1 (ANXA1), a Ca(2+) and phospholipid binding protein, is an important mediator of the antiinflammatory actions of glucocorticoids. However, although inflammatory responses in man are sensitive to alterations in adrenocortical function, the relationship between endogenous cortisol and ANXA1 expression has not been explored. Accordingly, we measured serum cortisol levels and ANXA1 expression in peripheral blood leukocytes from subjects with normal and dysregulated cortisol secretion before and 30 min after a standard corticotrophin (ACTH) test. Our data demonstrate a highly significant correlation between the serum cortisol concentration and the expression of ANXA1 in neutrophils, both before and after ACTH treatment, and thus suggest that ANXA1 may serve as a marker of glucocorticoid sensitivity. They also reveal a correlation between ANXA1 and the serum gonadotrophins, LH and FSH, and an age-related reduction in ANXA1 expression in lymphocytes.
