| First Author | Mittal D | Year | 2019 |
| Journal | Cancer Immunol Res | Volume | 7 |
| Issue | 4 | Pages | 559-571 |
| PubMed ID | 30894377 | Mgi Jnum | J:274776 |
| Mgi Id | MGI:6287993 | Doi | 10.1158/2326-6066.CIR-18-0637 |
| Citation | Mittal D, et al. (2019) CD96 Is an Immune Checkpoint That Regulates CD8(+) T-cell Antitumor Function. Cancer Immunol Res 7(4):559-571 |
| abstractText | CD96 is a novel target for cancer immunotherapy shown to regulate NK cell effector function and metastasis. Here, we demonstrated that blocking CD96 suppressed primary tumor growth in a number of experimental mouse tumor models in a CD8(+) T cell-dependent manner. DNAM-1/CD226, Batf3, IL12p35, and IFNgamma were also critical, and CD96-deficient CD8(+) T cells promoted greater tumor control than CD96-sufficient CD8(+) T cells. The antitumor activity of anti-CD96 therapy was independent of Fc-mediated effector function and was more effective in dual combination with blockade of a number of immune checkpoints, including PD-1, PD-L1, TIGIT, and CTLA-4. We consistently observed coexpression of PD-1 with CD96 on CD8(+) T lymphocytes in tumor-infiltrating leukocytes both in mouse and human cancers using mRNA analysis, flow cytometry, and multiplex IHF. The combination of anti-CD96 with anti-PD-1 increased the percentage of IFNgamma-expressing CD8(+) T lymphocytes. Addition of anti-CD96 to anti-PD-1 and anti-TIGIT resulted in superior antitumor responses, regardless of the ability of the anti-TIGIT isotype to engage FcR. The optimal triple combination was also dependent upon CD8(+) T cells and IFNgamma. Overall, these data demonstrate that CD96 is an immune checkpoint on CD8(+) T cells and that blocking CD96 in combination with other immune-checkpoint inhibitors is a strategy to enhance T-cell activity and suppress tumor growth. |
