Metabolic and Immune Cell Therapies in Combination with Radiotherapy for the Treatment of Non-Small Cell Lung Cancer

Abstract

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Despite advancements in treatments and earlier diagnoses, the prognosis for NSCLC remains poor, with an average 5-year survival rate of about 22%. Radiotherapy is essential in the management of NSCLC across all stages of the disease. However, its therapeutic potential is often constrained by resistance mechanisms and the risk of damage to healthy tissues. This thesis separately investigates the effects of two systemic therapies, canagliflozin and human epidermal growth factor receptor 2 (HER2)-targeted engineered T cells, in combination with radiotherapy for the treatment of NSCLC. It also aims to delineate the mechanisms by which these therapies exert their effects. We first demonstrate that canagliflozin, a drug originally approved for treating type 2 diabetes, exhibits tumor-suppressive activity and significantly augments the efficacy of radiotherapy in NSCLC. This enhancement occurs through various mechanisms, such as blocking mitochondrial respiration, activating AMP-activated protein kinase (AMPK), suppressing the mammalian target of rapamycin complex 1 (mTORC1)/hypoxia inducible factor-1 alpha (HIF-1a) pathway, and inducing substantial transcriptional reprogramming, likely through the inhibition of histone deacetylase 2 (HDAC2). We next demonstrate that radiotherapy and HER2-targeted engineered T cells synergistically suppress NSCLC tumor growth and prolong survival. Radiotherapy transiently increases HER2 expression in NSCLC tumors, which may contribute to the enhancement of HER2-targeted engineered T cell cytotoxic activity. However, the enhanced efficacy persists even when HER2-targeted engineered T cells are administered after HER2 levels return to baseline. Transcriptomics suggest that radiotherapy remodels the tumor microenvironment, creating an immunosupportive milieu conducive to activating T cell-mediated anti-tumor immunity. The findings presented in this thesis offer valuable insights that could inform the development of more effective therapeutic strategies for NSCLC.