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

Deepak Mittal, Ailin Lepletier, Jason Madore, Amelia Roman Aguilera, Kimberley Stannard, Stephen Blake, Vicki L.J. Whitehall, Cheng Liu, Mark L. Bettington, Kazuyoshi Takeda, Georgina V. Long, Richard A. Scolyer, Ruth Lan, Nathan Siemers, Alan Korman, Michele W.L. Teng, Robert J. Johnston, William C. Dougall, Mark J. Smyth

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

CD96 is a novel target for cancer immunotherapy shown to infiltrating leukocytes both in mouse and human cancers regulate NK cell effector function and metastasis. Here, we using mRNA analysis, flow cytometry, and multiplex IHF. demonstrated that blocking CD96 suppressed primary tumor The combination of anti-CD96 with anti–PD-1 increased growth in a number of experimental mouse tumor models in a the percentage of IFNg-expressing CD8 þ T lymphocytes. CD8 þ T cell–dependent manner. DNAM-1/CD226, Batf3, Addition of anti-CD96 to anti–PD-1 and anti-TIGIT resulted IL12p35, and IFNg were also critical, and CD96-deficient in superior antitumor responses, regardless of the ability of CD8 þ T cells promoted greater tumor control than CD96-the anti-TIGIT isotype to engage FcR. The optimal triple sufficient CD8 þ T cells. The antitumor activity of anti-CD96 combination was also dependent upon CD8 þ T cells and therapy was independent of Fc-mediated effector function IFNg. Overall, these data demonstrate that CD96 is an and was more effective in dual combination with blockade immune checkpoint on CD8 þ T cells and that blocking of a number of immune checkpoints, including PD-1, PD-L1, CD96 in combination with other immune-checkpoint inhi-TIGIT, and CTLA-4. We consistently observed coexpression bitors is a strategy to enhance T-cell activity and suppress of PD-1 with CD96 on CD8 þ T lymphocytes in tumor-tumor growth.

LanguageEnglish
Pages559-571
Number of pages13
JournalCancer Immunology Research
Volume7
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Cite this

Mittal, D., Lepletier, A., Madore, J., Aguilera, A. R., Stannard, K., Blake, S., ... Smyth, M. J. (2019). CD96 Is an Immune Checkpoint That Regulates CD8 + T-cell Antitumor Function. Cancer Immunology Research, 7(4), 559-571. https://doi.org/10.1158/2326-6066.CIR-18-0637
Mittal, Deepak ; Lepletier, Ailin ; Madore, Jason ; Aguilera, Amelia Roman ; Stannard, Kimberley ; Blake, Stephen ; Whitehall, Vicki L.J. ; Liu, Cheng ; Bettington, Mark L. ; Takeda, Kazuyoshi ; Long, Georgina V. ; Scolyer, Richard A. ; Lan, Ruth ; Siemers, Nathan ; Korman, Alan ; Teng, Michele W.L. ; Johnston, Robert J. ; Dougall, William C. ; Smyth, Mark J. / CD96 Is an Immune Checkpoint That Regulates CD8 + T-cell Antitumor Function. In: Cancer Immunology Research. 2019 ; Vol. 7, No. 4. pp. 559-571.
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abstract = "CD96 is a novel target for cancer immunotherapy shown to infiltrating leukocytes both in mouse and human cancers regulate NK cell effector function and metastasis. Here, we using mRNA analysis, flow cytometry, and multiplex IHF. demonstrated that blocking CD96 suppressed primary tumor The combination of anti-CD96 with anti–PD-1 increased growth in a number of experimental mouse tumor models in a the percentage of IFNg-expressing CD8 {\th} T lymphocytes. CD8 {\th} T cell–dependent manner. DNAM-1/CD226, Batf3, Addition of anti-CD96 to anti–PD-1 and anti-TIGIT resulted IL12p35, and IFNg were also critical, and CD96-deficient in superior antitumor responses, regardless of the ability of CD8 {\th} T cells promoted greater tumor control than CD96-the anti-TIGIT isotype to engage FcR. The optimal triple sufficient CD8 {\th} T cells. The antitumor activity of anti-CD96 combination was also dependent upon CD8 {\th} T cells and therapy was independent of Fc-mediated effector function IFNg. Overall, these data demonstrate that CD96 is an and was more effective in dual combination with blockade immune checkpoint on CD8 {\th} T cells and that blocking of a number of immune checkpoints, including PD-1, PD-L1, CD96 in combination with other immune-checkpoint inhi-TIGIT, and CTLA-4. We consistently observed coexpression bitors is a strategy to enhance T-cell activity and suppress of PD-1 with CD96 on CD8 {\th} T lymphocytes in tumor-tumor growth.",
author = "Deepak Mittal and Ailin Lepletier and Jason Madore and Aguilera, {Amelia Roman} and Kimberley Stannard and Stephen Blake and Whitehall, {Vicki L.J.} and Cheng Liu and Bettington, {Mark L.} and Kazuyoshi Takeda and Long, {Georgina V.} and Scolyer, {Richard A.} and Ruth Lan and Nathan Siemers and Alan Korman and Teng, {Michele W.L.} and Johnston, {Robert J.} and Dougall, {William C.} and Smyth, {Mark J.}",
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Mittal, D, Lepletier, A, Madore, J, Aguilera, AR, Stannard, K, Blake, S, Whitehall, VLJ, Liu, C, Bettington, ML, Takeda, K, Long, GV, Scolyer, RA, Lan, R, Siemers, N, Korman, A, Teng, MWL, Johnston, RJ, Dougall, WC & Smyth, MJ 2019, 'CD96 Is an Immune Checkpoint That Regulates CD8 + T-cell Antitumor Function', Cancer Immunology Research, vol. 7, no. 4, pp. 559-571. https://doi.org/10.1158/2326-6066.CIR-18-0637

CD96 Is an Immune Checkpoint That Regulates CD8 + T-cell Antitumor Function. / Mittal, Deepak; Lepletier, Ailin; Madore, Jason; Aguilera, Amelia Roman; Stannard, Kimberley; Blake, Stephen; Whitehall, Vicki L.J.; Liu, Cheng; Bettington, Mark L.; Takeda, Kazuyoshi; Long, Georgina V.; Scolyer, Richard A.; Lan, Ruth; Siemers, Nathan; Korman, Alan; Teng, Michele W.L.; Johnston, Robert J.; Dougall, William C.; Smyth, Mark J.

In: Cancer Immunology Research, Vol. 7, No. 4, 01.04.2019, p. 559-571.

Research output: Contribution to journalArticle

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T1 - CD96 Is an Immune Checkpoint That Regulates CD8 + T-cell Antitumor Function

AU - Mittal, Deepak

AU - Lepletier, Ailin

AU - Madore, Jason

AU - Aguilera, Amelia Roman

AU - Stannard, Kimberley

AU - Blake, Stephen

AU - Whitehall, Vicki L.J.

AU - Liu, Cheng

AU - Bettington, Mark L.

AU - Takeda, Kazuyoshi

AU - Long, Georgina V.

AU - Scolyer, Richard A.

AU - Lan, Ruth

AU - Siemers, Nathan

AU - Korman, Alan

AU - Teng, Michele W.L.

AU - Johnston, Robert J.

AU - Dougall, William C.

AU - Smyth, Mark J.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - CD96 is a novel target for cancer immunotherapy shown to infiltrating leukocytes both in mouse and human cancers regulate NK cell effector function and metastasis. Here, we using mRNA analysis, flow cytometry, and multiplex IHF. demonstrated that blocking CD96 suppressed primary tumor The combination of anti-CD96 with anti–PD-1 increased growth in a number of experimental mouse tumor models in a the percentage of IFNg-expressing CD8 þ T lymphocytes. CD8 þ T cell–dependent manner. DNAM-1/CD226, Batf3, Addition of anti-CD96 to anti–PD-1 and anti-TIGIT resulted IL12p35, and IFNg were also critical, and CD96-deficient in superior antitumor responses, regardless of the ability of CD8 þ T cells promoted greater tumor control than CD96-the anti-TIGIT isotype to engage FcR. The optimal triple sufficient CD8 þ T cells. The antitumor activity of anti-CD96 combination was also dependent upon CD8 þ T cells and therapy was independent of Fc-mediated effector function IFNg. Overall, these data demonstrate that CD96 is an and was more effective in dual combination with blockade immune checkpoint on CD8 þ T cells and that blocking of a number of immune checkpoints, including PD-1, PD-L1, CD96 in combination with other immune-checkpoint inhi-TIGIT, and CTLA-4. We consistently observed coexpression bitors is a strategy to enhance T-cell activity and suppress of PD-1 with CD96 on CD8 þ T lymphocytes in tumor-tumor growth.

AB - CD96 is a novel target for cancer immunotherapy shown to infiltrating leukocytes both in mouse and human cancers regulate NK cell effector function and metastasis. Here, we using mRNA analysis, flow cytometry, and multiplex IHF. demonstrated that blocking CD96 suppressed primary tumor The combination of anti-CD96 with anti–PD-1 increased growth in a number of experimental mouse tumor models in a the percentage of IFNg-expressing CD8 þ T lymphocytes. CD8 þ T cell–dependent manner. DNAM-1/CD226, Batf3, Addition of anti-CD96 to anti–PD-1 and anti-TIGIT resulted IL12p35, and IFNg were also critical, and CD96-deficient in superior antitumor responses, regardless of the ability of CD8 þ T cells promoted greater tumor control than CD96-the anti-TIGIT isotype to engage FcR. The optimal triple sufficient CD8 þ T cells. The antitumor activity of anti-CD96 combination was also dependent upon CD8 þ T cells and therapy was independent of Fc-mediated effector function IFNg. Overall, these data demonstrate that CD96 is an and was more effective in dual combination with blockade immune checkpoint on CD8 þ T cells and that blocking of a number of immune checkpoints, including PD-1, PD-L1, CD96 in combination with other immune-checkpoint inhi-TIGIT, and CTLA-4. We consistently observed coexpression bitors is a strategy to enhance T-cell activity and suppress of PD-1 with CD96 on CD8 þ T lymphocytes in tumor-tumor growth.

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EP - 571

JO - Cancer immunology research

T2 - Cancer immunology research

JF - Cancer immunology research

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