Role of lactic acid in the resistance to checkpoint inhibitors (anti-PD-1/PD-L1) used in cancer immunotherapy

• Grant number: 17/25308-9
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): September 01, 2018
• Effective date (End): August 31, 2021
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Fernando de Queiroz Cunha
• Grantee: Carlos Wagner de Souza Wanderley
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

The modulation of the immunological checkpoints with monoclonal antibodies anti-programmed cell death protein 1 (anti-PD-1), or anti-PD-1 ligand (anti-PD-L1) promotes the reactivation of antitumor immunity and produces unprecedented positive clinical responses in cancer treatment. However, 40-60% of patients presented a primary resistance to the anti-PD-1/PD-L1, which the mechanism is unknown. Currently, it is established in the literature that phenotypic and functional changes in immune cells are linked with metabolic adaptation. In line with this, it was demonstrated that lactic acid, a product of cellular glycolytic metabolism, inhibits CD8 T cell activation and favor the suppressor functions of the T regulatory cell through the increase of mitochondrial oxidative metabolism. Additionally, in the tumor microenvironment, the accumulation of lactic acid, a product from the glycolytic metabolism of neoplastic cells, was associated with the development of metastasis and less overall survival. These findings indicate that lactic acid is an immunosuppressive agent that participates of the tumor progression. However, the involvement of lactic acid in the resistance to anti-PD-1/PD-L1 treatment is still unknown. Therefore, we intend to investigate the role of lactic acid in the resistance to anti-PD-1/PD-L1 and to propose new immuno-pharmacological procedures that associated with checkpoint inhibitors could increase the efficacy of anti-cancer treatment.