Targeting the Warburg effect to overcome primary resistance to anti-PD-1/PD-L1 blockage

Abstract

Although primary resistance to anti-PD1/PD-L1 inhibitors is a common clinical event, the biological pathways underlying mechanisms are not fully understood. Currently, the potential correlation between the tumor glycolytic metabolism reprogramming, known as Warburg effect, and primary resistance to immune checkpoint inhibitors (ICIs) remains unknown. We propose that tumors with high glycolytic rates are more resistant to checkpoint inhibitors due to the competitive metabolic advantage and the immunosuppressive effect of lactate. We already found that cancer patients with primary resistance to treatment with ICIs have tumors with enrichment of genes linked to glycolysis and immunological signatures associated with Treg cells and M2 macrophages. In in vitro and in vivo assays we observed that tumor cells can directly restrict the availability of glucose to leukocytes infiltrating in the tumor. In parallel, we observed that the tumor microenvironment had reduced availability of glucose (<1mM) and marked accumulation of lactic acid (>12mM). This metabolic condition reduces the activation of cytotoxic CD8 cells and stimulates the differentiation of Treg and M2 macrophages. Furthermore, we observed that in the tumor of animals with hyperglycemia there is an accumulation of lactic acid in the tumor microenvironment and this condition was associated with resistance to immunotherapy with anti-PD1. Translationally, we confirm that patients with melanoma and non-small cell lung cancer (NSCLC) who have high metabolic glycolytic activity, measured by 18FDG-PET-SCAN, are resistant to treatment with ICIs. Collectively, the data obtained suggest that more glycolytic tumors are more resistant to this immunotherapy and that lactic acid, which is a product of tumor metabolism, has an immunosuppressive role that may be associated with this primary resistance to ICIs. Despite the relevant advances obtained in this project, we intend to further identify the mechanism that drives the Warburg effect to uncover novel biological targets or predictive biomarkers to boost the efficacy of ICIs therapy. In order to reach these aims, we have set up a collaborative study with Prof. Jennifer L. Guerriero from Harvard Medical School, which is expert in the field of cancer immunology and immunotherapy for instigate the role of BRCA1/PARP1 dependent-metabolic changes on primary resistance to ICIs. To this end, we are applying for the BEPE fellowship program to spend 12 months in his laboratory to develop this project. (AU)