Immunosuppressive enzymes in the tumor microenvironment

Abstract

Antigen encounter by T lymphocytes induces important metabolic changes. Antitumor T lymphocytes enter in a metabolic competition with tumors, which divert feedback mechanisms of the immune response. Immunosuppressive enzymes, modifying the nutrient availability and leading to the production of toxic catabolites, represent one of these mechanisms, contributing to the metabolic halo in which T lymphocytes evolve during immune responses. Two classes of immunosuppressive enzymes, expressed by the tumor cells or by cells of the microenvironment, have been described: those catabolizing essential or semiessential amino acids, tryptophan, arginine, and phenylalanine and the ectoenzymes, which degrade the ATP to produce adenosine. These enzymes are described, as well as some of the ongoing clinical trials aiming to block them in cancer treatment.

A Threshold Model for T-Cell Activation in the Era of Checkpoint Blockade Immunotherapy

“…However, there is increasing evidence suggesting that TDO can be produced by a variety of cancers, including hepatocellular carcinoma, glioma, melanoma, and others (94). In addition, recent studies have demonstrated that certain, specialized myeloid cells can express TDO and contribute to an immunosuppressive microenvironment (95, 96). The exact biologic and molecular basis for such a regulatory myeloid cell subset, however, is unclear.…”

Tissue-Specific Immunoregulation: A Call for Better Understanding of the “Immunostat” in the Context of Cancer

“…Another class of enzymes are the ectoenzymes expressed on the cell surface of T cells, CD39 and CD73. These dephosphorylate extracellular ATP, which is immunostimulatory, to adenosine, which is immunosuppressive (45). Heterogeneous expression of soluble mediators within organs may also contribute to organ-specific immunostats.…”

Reverting Immune Suppression to Enhance Cancer Immunotherapy

“…The US FDA has approved the clinical registration applications of IDO inhibitors, in 2016, PF-06840003 in the completed trial NCT02764151; in 2017, NLG802 in NCT03164603 and HTI-1090, respectively, in NCT03208959. Furthermore, combinational regimens with other treatment modalities are under evaluation (80), and some of them such as the phase I/II trial of indoximod combined with temozolomide, have shown promising results in patients with primary malignant brain tumors (NCT02052648). The completion of the safety and efficacy study evaluating indoximod in combination with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer (NCT02077881) revealed a promising activity as shown by the increased in intratumoral CD8+ T-cell density (poster presentation at the annual meeting of the American Society of Clinical Oncology 2018).…”