Cancer Sci. 2021 Jun 10. doi: 10.1111/cas.15020. Online ahead of print.
ABSTRACT
Despite immune checkpoint inhibitors(ICIs) have achieved unprecedented success in dMMR tumours, pMMR tumors accounting for 85% of colorectal cancer(CRC) cases remains unresponsive. Lactate dehydrogenase A(LDH-A) is the rate-limiting enzyme that catalyses the transformation of pyruvate to lactate in the process of glycolysis. We investigate the relationship between LDH-A and dMMR with the purpose of exploring the treatment strategy for pMMR CRC patients . We herein show that LDH-A can promote the proliferation of dMMR and pMMR CRC cells by positively regulating MMR proteins both in vitro and in vivo. LDH-A inhibition can improve the efficacy of PD-1 blockade in pMMR CRC xenograft model.. A statistical analysis of 186 CRC specimens showed a significant correlation between LDH-A and dMMR status. Moreover, patients with both low LDH-A expression and dMMR exhibited better disease free survival than patients with other combinations. The close correlation of LDH-A and dMMR may offer the promising therapeutic strategy that combination of LDH-A inhibitor and ICIs may improve the clinical benefit for pMMR CRC patients.
PMID:34110068 | DOI:10.1111/cas.15020
