Abstract
Abstract Tumor progression is facilitated by regulatory T cells (Treg) and restricted by effector T cells. In this study, we document parallel regulation of CD8+ T cells and Foxp3+ Tregs by programmed death-1 (PD-1, PDCD1). In addition, we identify an additional role of CTL antigen-4 (CTLA-4) inhibitory receptor in further promoting dysfunction of CD8+ T effector cells in tumor models (CT26 colon carcinoma and ID8-VEGF ovarian carcinoma). Two thirds of CD8+ tumor-infiltrating lymphocytes (TIL) expressed PD-1, whereas one third to half of CD8+ TIL coexpressed PD-1 and CTLA-4. Double-positive (PD-1+CTLA-4+) CD8+ TIL had characteristics of more severe dysfunction than single-positive (PD-1+ or CTLA-4+) TIL, including an inability to proliferate and secrete effector cytokines. Blockade of both PD-1 and CTLA-4 resulted in reversal of CD8+ TIL dysfunction and led to tumor rejection in two thirds of mice. Double blockade was associated with increased proliferation of antigen-specific effector CD8+ and CD4+ T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs, and upregulation of key signaling molecules critical for T-cell function. When used in combination with GVAX vaccination (consisting of granulocyte macrophage colony-stimulating factor–expressing irradiated tumor cells), inhibitory pathway blockade induced rejection of CT26 tumors in 100% of mice and ID8-VEGF tumors in 75% of mice. Our study indicates that PD-1 signaling in tumors is required for both suppressing effector T cells and maintaining tumor Tregs, and that PD-1/PD-L1 pathway (CD274) blockade augments tumor inhibition by increasing effector T-cell activity, thereby attenuating Treg suppression. Cancer Res; 73(12); 3591–603. ©2013 AACR.
Keywords
BlockadeCTLA-4Cancer researchDual (grammatical number)MedicineFunction (biology)Dual functionT cellPD-L1ImmunologyImmune systemImmunotherapyBiologyInternal medicineReceptorComputer scienceCell biology
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Publication Info
- Year
- 2013
- Type
- letter
- Volume
- 73
- Issue
- 12
- Pages
- 3591-3603
- Citations
- 724
- Access
- Closed
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Cite This
George Coukos,
Jaikumar Duraiswamy,
Karen M. Kaluza
et al.
(2013).
Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T-Cell Rejection Function in Tumors.
Cancer Research
, 73
(12)
, 3591-3603.
https://doi.org/10.1158/0008-5472.can-12-4100
Identifiers
- DOI
- 10.1158/0008-5472.can-12-4100