The Antitumor and Metabolomic Difference Between Male and Female Diet Induced Obese Mice Treated With Check Point Inhibitors
Authors: Erin E Trachet, BS, Chelsea Holmquist, MS, Paul Gonzales, PhD, Stephanie Nagl, MS and Ana Lemos de Matos, PhD
Abstract: Obesity is recognized as an epidemic, resulting in the dramatic rise of many diseases. Obesity is commonly associated with cardiovascular disease and diabetes, but we fail to recognize that obesity has been linked to at least 13 types of cancer, including breast and colon cancer.
In preclinical oncology studies, new treatments are tested in young, metabolically healthy mice of normal weight. To better represent the clinical population, we investigated tumor growth of commonly used murine cancer models implanted in diet induced obese C57BL/6 mice (male and female).
Methods: At the time of tumor cell implantation, mice (male and female) weighed over 40grs and were 18-21 weeks old. Accelerated tumor growth was observed in DIO mice compared to age-matched control mice in both syngeneic tumor models; MC38 murine colon carcinoma in male mice and EO771 murine breast carcinoma in female mice. To further evaluate the impact of the high fat diet on the mice and the tumors microenvironment we used both flow cytometry to assess the immune profile and proteomic and metabolic analysis.
Results: We evaluated the response to anti-mPD-1 treatment in the MC38 model comparing DIO mice with control diet (CD) mice. DIO mice in the MC38 model exhibited a robust anti-tumor response (TGI=53%) compared to no response observed in CD mice (TGI=0%). In the EO771 model, anti-mCTLA-4 and anti-mPD-1 treatment was highly effective in DIO mice, resulting in >70% tumor growth inhibition (TGI) and tumor stagnation during the treatment window. whereas anti-mPD-1 treatment showed no response in CD mice (TGI=0%). Analysis of the TME in both models revealed marked difference in immune cell populations when comparing the DIO mice to the CD mice and when compare the male (MC38) to the female (EO771) models. Metabolomic analysis revealed shifts in certain glycolysis pathways indicating a shift in dependency of the models fed the high fat diet.
