Regulation of the tumor immune microenvironment and vascular normalization in TNBC murine models by a novel peptide
| Autor: | Vered Stearns, Evanthia T. Roussos Torres, Aleksander S. Popel, Brian J. Christmas, Christine I. Rafie, Elizabeth M. Jaffee, Akash Patil, Niranjan B. Pandey, Adam C. Mirando |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Immune microenvironment Immunology Peptide Triple Negative Breast Neoplasms Aggressive disease 03 medical and health sciences Mice 0302 clinical medicine Breast cancer Atezolizumab Tumor Microenvironment Immunology and Allergy Medicine Animals Humans Triple-negative breast cancer RC254-282 immunomodulating peptide vascular normalization Original Research chemistry.chemical_classification Mice Inbred BALB C tumor immune microenvironment business.industry Treatment options Neoplasms. Tumors. Oncology. Including cancer and carcinogens Vascular normalization RC581-607 medicine.disease Disease Models Animal 030104 developmental biology Oncology chemistry 030220 oncology & carcinogenesis Cancer research triple-negative breast cancer Immuno-activation Immunologic diseases. Allergy business Peptides Research Article |
| Zdroj: | Oncoimmunology article-version (VoR) Version of Record OncoImmunology, Vol 9, Iss 1 (2020) |
| ISSN: | 2162-4011 |
| Popis: | Triple-negative breast cancer (TNBC) is a highly metastatic and aggressive disease with limited treatment options. Recently, the combination of the immune checkpoint inhibitor (ICI) atezolizumab (anti-PD-L1) with nab-paclitaxel was approved following a clinical trial that showed response rates in at least 43% of patients. While this approval marks a major advance in the treatment of TNBC it may be possible to improve the efficacy of ICI therapies through further modulation of the suppressive tumor immune microenvironment (TIME). Several factors may limit immune response in TNBC including aberrant growth factor signaling, such as VEGFR2 and cMet signaling, inefficient vascularization, poor delivery of drugs and immune cells, and the skewing of immune cell populations toward immunosuppressive phenotypes. Here we investigate the immune-modulating properties of AXT201, a novel 20 amino-acid integrin-binding peptide in two syngeneic mouse TNBC models: 4T1-BALB/c and NT4-FVB. AXT201 treatment improved survival in the NT4 model by 20% and inhibited the growth of 4T1 tumors by 47% over 22 days post-inoculation. Subsequent immunohistochemical analyses of 4T1 tumors also showed a 53% reduction in vascular density and a 184% increase in pericyte coverage following peptide treatment. Flow cytometry analyses demonstrated evidence of a more favorable anti-tumor immune microenvironment following treatment with AXT201, including significant decreases in the populations of T regulatory cells, monocytic myeloid-derived suppressor cells, and PD-L1 expressing cells and increased expression of T cell functional markers. Together, these findings demonstrate immune-activating properties of AXT201 that could be developed in combination with other immunomodulatory agents in the treatment of TNBC. |
| Databáze: | OpenAIRE |
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