| First Author | Chatterjee S | Year | 2014 |
| Journal | Cancer Res | Volume | 74 |
| Issue | 21 | Pages | 6048-59 |
| PubMed ID | 25205101 | Mgi Jnum | J:216686 |
| Mgi Id | MGI:5609216 | Doi | 10.1158/0008-5472.CAN-14-1450 |
| Citation | Chatterjee S, et al. (2014) Reducing CD73 expression by IL1beta-Programmed Th17 cells improves immunotherapeutic control of tumors. Cancer Res 74(21):6048-59 |
| abstractText | T cells of the T helper (Th)17 subset offer promise in adoptive T-cell therapy for cancer. However, current protocols for ex vivo programming of Th17 cells, which include TGFbeta exposure, increase the expression of CD39 and CD73, two cell surface ATP ectonucleotidases that reduce T-cell effector functions and promote immunosuppression. Here, we report that ATP-mediated suppression of IFNgamma production by Th17 cells can be overcome by genetic ablation of CD73 or by using IL1beta instead of TGFbeta to program Th17 cells ex vivo. Th17 cells cultured in IL1beta were also highly polyfunctional, expressing high levels of effector molecules and exhibiting superior short-term control of melanoma in mice, despite reduced stem cell-like properties. TGFbeta addition at low doses that did not upregulate CD73 expression but induced stemness properties drastically improved the antitumor effects of IL1beta-cultured Th17 cells. Effector properties of IL1beta-dependent Th17 cells were likely related to their high glycolytic capacity, since ex vivo programming in pyruvate impaired glycolysis and antitumor effects. Overall, we show that including TGFbeta in ex vivo cultures used to program Th17 cells blunts their immunotherapeutic potential and demonstrate how this potential can be more fully realized for adoptive T-cell therapy. |
