Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T Journal Article
| Authors: | Burga, R. A.; Thorn, M.; Point, G. R.; Guha, P.; Nguyen, C. T.; Licata, L. A.; DeMatteo, R. P.; Ayala, A.; Joseph Espat, N.; Junghans, R. P.; Katz, S. C. |
| Article Title: | Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T |
| Abstract: | Chimeric antigen receptor-modified T cell (CAR-T) technology, a promising immunotherapeutic tool, has not been applied specifically to treat liver metastases (LM). While CAR-T delivery to LM can be optimized by regional intrahepatic infusion, we propose that liver CD11b+Gr-1+ myeloid-derived suppressor cells (L-MDSC) will inhibit the efficacy of CAR-T in the intrahepatic space. We studied anti-CEA CAR-T in a murine model of CEA+ LM and identified mechanisms through which L-MDSC expand and inhibit CAR-T function. We established CEA+ LM in mice and studied purified L-MDSC and responses to treatment with intrahepatic anti-CEA CAR-T infusions. L-MDSC expanded threefold in response to LM, and their expansion was dependent on GM-CSF, which was produced by tumor cells. L-MDSC utilized PD-L1 to suppress anti-tumor responses through engagement of PD-1 on CAR-T. GM-CSF, in cooperation with STAT3, promoted L-MDSC PD-L1 expression. CAR-T efficacy was rescued when mice received CAR-T in combination with MDSC depletion, GM-CSF neutralization to prevent MDSC expansion, or PD-L1 blockade. As L-MDSC suppressed anti-CEA CAR-T, infusion of anti-CEA CAR-T in tandem with agents targeting L-MDSC is a rational strategy for future clinical trials. © 2015, Springer-Verlag Berlin Heidelberg. |
| Keywords: | protein expression; splenectomy; nonhuman; flow cytometry; t lymphocyte; mouse; stat3 protein; granulocyte macrophage colony stimulating factor; animal experiment; animal model; antineoplastic activity; liver metastasis; cd11b antigen; western blotting; chimeric antigen receptor; macrophage; bioluminescence; cd45 antigen; suppressor cell; immunosuppression; programmed death 1 ligand 1; programmed death 1 receptor; gm-csf; liver metastases; glycoprotein p 15095; myeloid derived suppressor cell; male; priority journal; article; car-t; mdsc |
| Journal Title: | Cancer Immunology, Immunotherapy |
| Volume: | 64 |
| Issue: | 7 |
| ISSN: | 0340-7004 |
| Publisher: | Springer |
| Date Published: | 2015-07-01 |
| Start Page: | 817 |
| End Page: | 829 |
| Language: | English |
| DOI: | 10.1007/s00262-015-1692-6 |
| PROVIDER: | scopus |
| PMCID: | PMC4485571 |
| PUBMED: | 25850344 |
| DOI/URL: | |
| Notes: | Export Date: 3 August 2015 -- Source: Scopus |
