Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy

Raghavan, Sukanya,1974Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för mikrobiologi och immunologi,Institute of Biomedicine, Department of Microbiology and Immunology (author)

Programmed cell death-1 (PD-1) blockade has a profound effect on the ability of the immune system to eliminate tumors, but many questions remain about the cell types involved and the underlying mechanisms of immune activation. To shed some light on this, the cellular and molecular events following inhibition of PD-1 signaling was investigated in the MC-38 colon carcinoma model using constitutive (PD-1 KO) and conditional (PD1cKO) mice and in wild-type mice treated with PD-1 antibody. The impact on both tumor growth and the development of tumor immunity was assessed. In the PD-1cKO mice, a complete deletion of Pdcd1 in tumor-infiltrating T cells (TILs) after tamoxifen treatment led to the inhibition of tumor growth of both small and large tumors. Extensive immune phenotypic analysis of the TILs by flow and mass cytometry identified 20-different T cell subsets of which specifically 5-CD8 positive ones expanded in all three models after PD-1 blockade. All five subsets expressed granzyme B and interferon gamma (IFN gamma). Gene expression analysis of the tumor further supported the phenotypic analysis in both PD-1cKO- and PD-1 Ab-treated mice and showed an upregulation of pathways related to CD4 and CD8 T-cell activation, enhanced signaling through costimulatory molecules and IFN gamma, and non-T-cell processes. Altogether, using PD-1cKO mice, we define the intrinsic nature of PD-1 suppression of CD8 T-cell responses in tumor immunity.

Tovbis-Shifrin, N. (author)
Kochel, C. (author)
Sawant, A. (author)
Mello, M. (author)
Sathe, M. (author)
Blumenschein, W. (author)
Muise, E. S. (author)
Chackerian, A. (author)
Pinheiro, E. M. (author)
Rosahl, T. W. (author)
Luche, H. (author)
Malefyt, R. D. (author)
Göteborgs universitetInstitutionen för biomedicin, avdelningen för mikrobiologi och immunologi (creator_code:org_t)

By the author/editor: Raghavan, Sukany ...; Tovbis-Shifrin, ...; Kochel, C.; Sawant, A.; Mello, M.; Sathe, M.; show more...; Blumenschein, W.; Muise, E. S.; Chackerian, A.; Pinheiro, E. M.; Rosahl, T. W.; Luche, H.; Malefyt, R. D.; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Immunology in th ...

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