Abstract 2082: Obesity dependent benefits of metformin for improved anti-tumor immunity and outcomes in non-small cell lung cancer
Authors: Barbi Joseph , Smith Randall J. , Zollo Robert , Sass Stephanie N. , Washington Deschana , Petrucci Cara , Srinivasan Aravind , Kannisto Eric , Patnaik Santosh , Yendamuri Sai Sai 
Published: June 2022

Abstract
Metformin, the widely used and studied diabetes drug, has been reported to have anti-cancer effects. However, in retrospective clinical studies, the survival benefit associated with metformin use in cancer patients is often modest. Consequently, the design and conduct of sufficiently powered prospective clinical trials aimed at exploring this drug’s anti-tumor potential are hampered by the absence of predictive biomarkers. Testing the notion that specific patient characteristics such as obesity may impact the relative potency of metformin’s effects on lung cancer survival, we analyzed the patient outcomes of 756 non-small cell lung cancer (NSCLC) cases with early- (stage I/II, n = 490) or late-stage disease (stage III/IV, n = 266) that either did or did not use metformin (n = 121 and 635, respectively) while not receiving neoadjuvant therapy. We found that metformin use is associated with improved overall and recurrence free survival only in overweight and obese patients defined by a body mass index (BMI) greater than 25 kg/m2. Corroborative findings obtained from immunocompetent mouse lung cancer models aligned with these observations. In these studies, despite supporting accelerated growth of both primary and metastatic tumors compared to their normal weight counterparts, animals subjected to diet induced obesity (DIO) experienced significantly reduced tumor development upon metformin treatment. In contrast, the drug had little-to-no effect on tumor burden in normal weight controls. Furthermore, while flow cytometric evaluation of obese mouse-derived tumors identified several previously described mediators of immune dysfunction previously described in animals with DIO (e.g., widespread up-regulation of the immune checkpoint factors PD-1 and Lag3, elevated suppressor cell proportions and activity), metformin treatment was associated with their reversal specifically in the tumors of obese mice. Interestingly, the drug had little effect on the tumor immune contexture of normal weight mice, and gene expression analysis failed to reveal considerable alterations in canonical cancer pathways. Thus, our preclinical and clinical studies suggest that the anti-diabetic drug metformin has an anti-cancer effect in NSCLC that is restricted to overweight individuals and reflects its potential to direct favorable, context-specific immune reprogramming. This work also provides the rationale for using high BMI as a predictive biomarker of the anti-cancer effect of metformin in lung cancer.
Citation Format: Joseph Barbi, Randall J. Smith, Robert Zollo, Stephanie N. Sass, Deschana Washington, Cara Petrucci, Aravind Srinivasan, Eric Kannisto, Santosh Patnaik, Sai Sai Yendamuri. Obesity dependent benefits of metformin for improved anti-tumor immunity and outcomes in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2082.