CD96 Is an Immune Checkpoint That Regulates CD8+ T-cell Antitumor Function

  • Cancer Immunol Res. 2019 Apr;7(4):559-571. doi: 10.1158/2326-6066.CIR-18-0637.
Deepak Mittal  #  1 ,  Ailin Lepletier  #  1 ,  Jason Madore  1 ,  Amelia Roman Aguilera  1 ,  Kimberley Stannard  1 ,  Stephen J Blake  2 ,  Vicki L J Whitehall  3  4 ,  Cheng Liu  3  4  5 ,  Mark L Bettington  5 ,  Kazuyoshi Takeda  6  7 ,  Georgina V Long  8  9  10 ,  Richard A Scolyer  8  10 ,  Ruth Lan  11 ,  Nathan Siemers  11 ,  Alan Korman  11 ,  Michele W L Teng  2 ,  Robert J Johnston  11 ,  William C Dougall  #  1 ,  Mark J Smyth  #  12
Affiliations
  • 1. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
  • 2. Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
  • 3. The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
  • 4. Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia.
  • 5. Envoi Specialist Pathologists, Kelvin Grove, Queensland, Australia.
  • 6. Division of Cell Biology, Biomedical Research Center, Juntendo University, Bunkyo-ku, Tokyo, Japan.
  • 7. Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan.
  • 8. Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
  • 9. Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
  • 10. The University of Sydney, New South Wales, Australia.
  • 11. Bristol-Myers Squibb, New York, New York.
  • 12. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. [email protected].
  • # Contributed equally.
PMID: 30894377 DOI: 10.1158/2326-6066.CIR-18-0637
Abstract

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 IFNγ 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 IFNγ-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 IFNγ. 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.

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