Recent findings about the new roles of lactate have changed our understanding of this end product of glycolysis or fermentation that was once considered only a waste product. It is now well accepted that lactate acts as a signaling molecule and fuel source for cancer cells in a glucose-restricted environment. Moreover, lactate and lactate dehydrogenase are markers of poor prognosis of many cancers and regulate many functions of immune cells. The presence of lactate in the tumor microenvironment (TME) leads to polarization of the immunosuppressive phenotypes of dendritic cells and impairs the cytotoxic abilities of T cells and NK cells, and as such lactate is a major obstacle to immune-cell effector functions and the efficacy of cell-based immunotherapies. Emerging evidence suggests that lactate in the TME might be a novel therapeutic target to enhance the immunotherapeutic potential of cell-based therapies. This review describes our current understanding of the role of lactate in tumor biology, including its detrimental effects on cell-based immunotherapy in cancer. We also highlight how the role of lactate in the TME must be considered when producing cell therapies designed for adoptive transfer and describe how targeted modulation of lactate in the TME might boost immune-cell functions and positively impact cellular immunotherapy, with a focus on NK cell.

• Keywords
• NK cell, T cell, cytotoxicity, immunometabolism, immunosuppression,, immunotherapy, lactate,
• MeSH
• Killer Cells, Natural MeSH
• Immunotherapy MeSH
• Lactic Acid MeSH
• Humans MeSH
• Tumor Microenvironment * MeSH
• Neoplasms * therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Lactic Acid MeSH

Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts. We performed biomolecular and cytofluorometric analyses on peripheral blood samples collected prior to immunotherapy from 1000 patients enrolled in these trials, with the objective of identifying immunological biomarkers that may improve the clinical management of DCVAC-treated patients. Gene signatures reflecting adaptive immunity and T cell activation were associated with favorable disease outcomes and responses to DCVAC in patients with prostate and lung cancer, but not ovarian carcinoma. By contrast, the clinical benefits of DCVAC were more pronounced among patients with ovarian carcinoma exhibiting reduced expression of T cell-associated genes, especially those linked to TH2-like signature and immunosuppressive regulatory T (TREG) cells. Clinical responses to DCVAC were accompanied by signs of antitumor immunity in the peripheral blood. Our findings suggest that circulating signatures of antitumor immunity may provide a useful tool for monitoring the potency of autologous DC-based immunotherapy.

• Keywords
• Cancer immunotherapy, anti-PD-1, circulating biomarkers, epithelial ovarian carcinoma, metastatic castrate-resistant prostate cancer, non-small cell lung carcinoma,
• MeSH
• Dendritic Cells metabolism   MeSH
• Carcinoma, Ovarian Epithelial drug therapy   MeSH
• Humans MeSH
• Lung Neoplasms * drug therapy   therapy   MeSH
• Ovarian Neoplasms * genetics   therapy   MeSH
• Cancer Vaccines * therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cancer Vaccines * MeSH