AACR 2023 Poster
Antitumor and metabolomic evaluation of immune checkpoint inhibition in diet-induced obese mice
Poster Section: 36 – Poster #11
Abstract Presentation Number: #9861
Authors: Michael Boice, Whitney Tuoti, Logan Chesney, Maggie Murray, Paul M. Gonzales, Stephen T. Gately. Translational Drug Development, Scottsdale, AZ
Abrstract: Obesity is an epidemic in the Western world and a risk factor for at least 13 types of cancer. Cancer rates are rising for several obesity-related cancers, such as liver, pancreatic, thyroid, and uterine, as well as for colorectal cancer in patients under 55. Preclinical studies for new cancer drugs are often performed in models of cancer that are hosted in mice that are metabolically healthy and of normal weight.
To establish models of cancer in hosts that are more reflective of the clinical population, we established the tumor growth kinetics of commonly used murine models of cancer in diet induced obese (DIO) mice. Syngeneic tumor models, MC38 and Hepa1-6, implanted in 18-week-old DIO C57BL6 mice showed accelerated tumor growth when compared to the growth rate in age-match control C57BL6 mice. We also studied the growth of three other C57BL/6J syngeneic tumor models; MB49, TC-1 and PAN 02. Interestingly, pancreatic PAN 02 demonstrated slower growth in DIO mice compared to age matched controls. We then tested the response of anti-mPD-1 (αPD-1) against MC38 syngeneic mouse tumor model comparing response of αPD-1 in 18-week-old DIO mice versus age matched control diet (CD) mice. The αPD-1 treatment showed a strong anti-tumor response (TGI=53%) against MC38 in DIO mice in contrast to no response (TGI=0%) in CD mice. Evaluation of the tumor microenvironment (TME) on Day 13 revealed comparable numbers of CD8+ T Cells in 18-week-old DIO mice tumors compared to CD tumors. Treatment with αPD-1 resulted in a statistically significant increase in CD8+ T Cells in DIO mouse tumors compared to CD tumors (p<0.008). An increase in LAG3+ cells were detected in αPD-1 treated DIO tumors compared to CD (p<0.05). A global metabolomics assessment of serum metabolites showed significant alterations in metabolites between CD and DIO mice. DIO αPD-1 treated mice had 88 metabolites significantly altered compared to only 16 metabolites in CD αPD-1 treated mice. Thirty-six metabolites increased after αPD-1 treatment in DIO mice but were decreased after αPD-1 treatment in CD mice. Amongst these 36 metabolites were alterations in the pentose phosphate pathway particularly with ribose 5-phospate and sedoheptulose 1-phosphate intermediates. DIO accelerated MC38 tumor growth and showed improved sensitivity to αPD-1 treatment compared to CD in 18-week-old mice. The significant increase in LAG3+ cells in the TME of DIO MC38 tumors treated with αPD-1 could represent an opportunity for greater antitumor efficacy of αPD-1treatment combined with anti-LAG3 in DIO mice. Use of syngeneic tumor models in DIO mice may provide improved models for identification and development of immunomodulatory, or other cancer therapeutics in a more metabolically challenged, clinically relevant system. These models could also permit the detection of novel circulating metabolites that could be targets for therapeutic development to improve treatment efficacy.