Arginase Therapy Combines Effectively with Immune Checkpoint Blockade or Agonist Anti-OX40 Immunotherapy to Control Tumor Growth
| Autor: | Danlee Enzler, Annah S Rolig, James E. Wooldridge, Mark R. Sullivan, Christopher L. Daige, Scott W. Rowlinson, Jason F. Wiggins, Leslie Priddy, Giulia Agnello, Melissa J Kasiewicz, Matthew G. Vander Heiden, Jessica Van Cleef, Venkatesh Rajamanickam, William L. Redmond, Alexander Muir, Mark Badeaux |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Agonist Cancer Research Combination therapy Arginine medicine.drug_class medicine.medical_treatment Immunology Antigen presentation Programmed Cell Death 1 Receptor Antineoplastic Agents CD8-Positive T-Lymphocytes 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Cell Line Tumor medicine Animals Humans Immune Checkpoint Inhibitors Mice Inbred BALB C Arginase business.industry Immunotherapy Ornithine Receptors OX40 Adoptive Transfer Mice Inbred C57BL Disease Models Animal 030104 developmental biology chemistry 030220 oncology & carcinogenesis Cancer research Female business CD8 Neoplasm Transplantation |
| Zdroj: | Cancer immunology research. 9(4) |
| ISSN: | 2326-6074 |
| Popis: | Metabolic dysregulation is a hallmark of cancer. Many tumors exhibit auxotrophy for various amino acids, such as arginine, because they are unable to meet the demand for these amino acids through endogenous production. This vulnerability can be exploited by employing therapeutic strategies that deplete systemic arginine in order to limit the growth and survival of arginine auxotrophic tumors. Pegzilarginase, a human arginase-1 enzyme engineered to have superior stability and enzymatic activity relative to the native human arginase-1 enzyme, depletes systemic arginine by converting it to ornithine and urea. Therapeutic administration of pegzilarginase in the setting of arginine auxotrophic tumors exerts direct antitumor activity by starving the tumor of exogenous arginine. We hypothesized that in addition to this direct effect, pegzilarginase treatment indirectly augments antitumor immunity through increased antigen presentation, thus making pegzilarginase a prime candidate for combination therapy with immuno-oncology (I-O) agents. Tumor-bearing mice (CT26, MC38, and MCA-205) receiving pegzilarginase in combination with anti–PD-L1 or agonist anti-OX40 experienced significantly increased survival relative to animals receiving I-O monotherapy. Combination pegzilarginase/immunotherapy induced robust antitumor immunity characterized by increased intratumoral effector CD8+ T cells and M1 polarization of tumor-associated macrophages. Our data suggest potential mechanisms of synergy between pegzilarginase and I-O agents that include increased intratumoral MHC expression on both antigen-presenting cells and tumor cells, and increased presence of M1-like antitumor macrophages. These data support the clinical evaluation of I-O agents in conjunction with pegzilarginase for the treatment of patients with cancer. |
| Databáze: | OpenAIRE |
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