Use of gastrin vaccine to increase gamma-delta and NKT cells and alter pancreas tumor microenvironment to improve survival
| Autor: | Jill P Smith, Nicholas Osborne, Rebecca Sundseth, Hong Cao, Martha D Gay, Robin D. Tucker, Alexander H Kroemer, Lynda Youngpeter Sutton, Allen Cato |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 38:696-696 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2020.38.4_suppl.696 |
| Popis: | 696 Background: Pancreatic cancer (PC) has been called a “cold” tumor as it responds poorly to immune-based therapies. Strategies to render PC susceptible to immunotherapy are under investigation by methods that alter immune cell signatures such as increasing the population of double negative CD4-CD8-T-cells, or changing the polarization of tumor-associated macrophages (TAMs). Our current aim was to determine if a gastrin vaccine, Polyclonal Antibody Stimulator (PAS) influences double negative T-cell phenotype and polarization of TAMs to improve survival of PC. Methods: Two cohorts of C57BL/6 mice were injected either sc or orthotopically with syngeneic mT3 murine pancreatic cancer cells. After 1 week, groups were treated with PBS; PAS (100μg); PD-1 antibody (150μg); or the combination of PAS and PD-1 Ab. PAS was given ip at weeks 0, 1 and 3. Anti-PD-1 was given on days 0, 4, 8, 15 and 21. Spleens were collected from the sc experiment for T-cell surface analysis by flow cytometry. Orthotopic tumors were measured for growth rate, metastases, and stained for M1 (inos) and M2 (arginase) polarized TAMs, and mouse survival was analyzed. Results: PAS therapy increased expression of double negative T-cells. The percentage of gamma-delta T-cells in the (CD3+/CD4−/CD8−/CD44−/CD62L−) TEMRA subpopulation of mice treated with PAS or combinations of PAS with PD-1 Ab were increased approximately 40% compared to PBS-treated controls or PD-1 Ab-treated mice. NKT cells from PAS-vaccinated mice were 2.5-fold higher than controls. M2+ TAMS were significantly decreased in tumors of PAS treated mice compared to PBS treated mice (p = 0.017). PAS monotherapy resulted in a nearly 10-fold increase in M1 TAMs relative to controls (p = 0.002). PAS monotherapy decreased tumor metastases by 69% and prolonged survival. Primary tumor growth decreased with PAS in combination with PD-1 Ab (p=0.0025). Conclusions: PAS decreases PC tumor growth and metastases by increasing CD4-CD8-, gamma-delta, and NKT T-cell populations. Furthermore, PAS monotherapy significantly increases M1 and decreases M2 TAMs. These immune cell changes with PAS vaccination may render tumors more susceptible to other cancer therapies and improve survival. |
| Databáze: | OpenAIRE |
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