Although immune checkpoint inhibitors (ICIs) have achieved unprecedented success in dMMR tumors, pMMR tumors accounting for 85% of colorectal cancer (CRC) cases remain unresponsive. Lactate dehydrogenase A (LDH-A) is the rate-limiting enzyme that catalyzes the transformation of pyruvate to lactate in the process of glycolysis. We investigated the relationship between LDH-A and dMMR with the purpose of exploring the treatment strategy for pMMR CRC patients. We here 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 a 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 compared with patients with other combinations. The close correlation of LDH-A and dMMR may offer a promising therapeutic strategy in which the combination of LDH-A inhibitor and ICIs may improve the clinical benefit for pMMR CRC patients.
Keywords: colorectal cancer; disease-free survival; lactate dehydrogenase A (LDH-A); mismatch-repair-deficient (dMMR); mismatch-repair-proficient (pMMR).
© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.