Posted: Tuesday, May 10, 2022
Mutations that result in the loss of function of the tumor suppressor serine/threonine kinase STK11/LKB1 are present in approximately 30% of lung adenocarcinomas and are known to be drivers of treatment resistance. LKB1 mutations promote higher hypoxia and glycolysis rates in non–small cell lung cancer (NSCLC), causing lactate production and secretion to increase significantly. Hypothesizing that blocking the lactate pathway could promote the efficacy of immune checkpoint inhibitors, John Heymach, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues created knockout mutations targeting LKB1 kinase and the MCT4 lactate transporter to evaluate the therapeutic strategy. The results of the study, which were presented at the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 2160), suggested the therapeutic inhibition of MCT4 may help to correct elevated glycolysis rates and resistance triggered by LKB1 mutations.
Prior to creating the knockout cell lines, the investigators analyzed clinical data from patients with NSCLC who were originally enrolled in the MD Anderson Cancer Center’s ICON and PROSPECT cohorts. Tumors with LKB1 mutations appeared to have lower immune cell infiltration, restricted T-cell function, and enhanced M2-like macrophages in addition to higher glycolysis rates and enhanced MCT4 expression.
When MCT4 was deleted, however, glycolysis was dramatically reduced, along with energy production and cell proliferation. Using single-cell RNA sequencing, the investigators identified immune subclusters modulated by LKB1 mutations. It was noted that the deletion seemed to correct the dysfunctional T cells and M2-like macrophages present in LKB1-mutant tumors. However, when exogenous lactate was introduced, these effects were reversed. Lastly, the MCT4 knockout sensitized tumors to anti–PD-1 immunotherapy, suggesting that MCT4 inhibition may be potentially beneficial in reversing the immunotherapy resistance created by LKB1 mutations.
Disclosure: For full disclosures of the study authors, visit abstractsonline.com.