2. Academic Validation
  3. CD96 Is an Immune Checkpoint That Regulates CD8+ T-cell Antitumor Function

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

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. mark.smyth@qimrberghofer.edu.au.
  • # 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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