Lactic Acid Supports an Immunosuppressive Environment and Reduces ICB Response

Immune checkpoint blockade (ICB) therapy, such as anti–PD-1 antibodies, have shown promise, but resistance continues to remain an issue. Recent reports have indicated that the expression balance between PD-1–expressing CD8⁺ cytotoxic T cells and T regulatory cells (Treg) in the tumor microenvironment (TME) can be a predictive biomarker for ICB response; however, the factors that determine this balance are currently not known. Kumagai and colleagues addressed this by assessing metabolic profiles between PD-1–expressing effector T cells and Tregs in the TME, showing that the ratio of tumor-infiltrating CD8⁺ T cells to Tregs was lower as was the PD-1 expression on CD8⁺ T cells in MYC-overexpressing gastric and non–small cell lung cancer. Similar results were observed in highly glycolytic liver metastatic lesions. Investigation into the mechanisms by which Tregs gained higher PD-1 expression in highly glycolytic tumors revealed that lactic acid (LA), which is high in glycolytic tumors as it is the final product of glycolysis, could enhance PD-1 expression in Tregs, but not CD8⁺ T cells, through the LA transporter monocarboxylate transporter 1 (MCT1), with MCT1 expression being directly promoted by FOXP3. Use of PD-1 blockade in a high-LA microenvironment showed an increase in the suppressive activities of Tregs, contributing to a much stronger suppressor to effector function. In a model of Myc-overexpressing murine colon carcinoma, higher amounts of LA production contributed to an increase in Treg PD-1 expression and subsequent ICB treatment resistance. This resistance to PD-1 blockade could be overcome by blocking tumor LA production or MCT1 in Tregs, while expression of lactate dehydrogenase A or MYC was associated with a reduction in progression-free survival in patients with gastric cancer, non–small cell lung cancer, or malignant melanoma. This study demonstrates an immunosuppressive function of LA in the TME and supports its targeting to improve immunotherapy response in highly glycolytic or MYC-overexpressing tumors.

Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 2022 Jan 25 [Epub ahead of print].

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.