Journal
MOLECULAR THERAPY
Volume 29, Issue 1, Pages 60-74Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2020.09.034
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Funding
- National Natural Science Foundation of China [31800659]
- Shanghai Sailing Program [18YF1422000]
- Shanghai Science and Technology Innovation Action Plan [18431902900]
- Project of Shanghai Municipal Health Commission [201940118]
- Shanghai Cancer Institute [SB18-05]
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This study demonstrates that the PARPi olaparib can significantly enhance the efficacy of CAR-T cells in breast cancer models by inhibiting MDSC migration, indicating a potential novel mechanism for combination therapy in breast cancer treatment.
A hostile tumor microenvironment is one of the major obstacles for the efficacy of chimeric antigen receptor modified T (CAR-T) cells, and combination treatment might be a potential way to overcome this obstacle. Poly(ADP-ribose) polymerase inhibitor (PARPi) has demonstrated tremendous potential in breast cancer. In this study, we explored the possible combination of the PAPRi olaparib with EGFRvIII-targeted CAR (806-28Z CAR) T cells in immunocompetent mouse models of breast cancer. The results indicated that the administration of olaparib could significantly enhance the efficacy of 806-28Z CAR-T cells in vivo. Interestingly, we observed that olaparib could suppress myeloid-derived suppressor cell (MDSC) migration and promote the survival of CD8(+) T cells in tumor tissue. Mechanistically, olaparib was shown to reduce the expression of SDF1 alpha released from cancer-associated fibroblasts (CAFs) and thereby decreased MDSC migration through CXCR4. Taken together, this study demonstrated that olaparib could increase the antitumor activities of CAR-T cell therapy at least partially through inhibiting MDSC migration via the SDF1 alpha/CXCR4 axis. These findings uncover a novel mechanism of PARPi function and provide additional mechanistic rationale for combining PARPi with CAR-T cells for the treatment of breast cancer.
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