Journal
CANCER RESEARCH
Volume 72, Issue 4, Pages 917-927Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-11-1620
Keywords
-
Categories
Funding
- NIH [R01 AI39480, R01 CA127153, P50 CA58236-15]
- Hartwell Postdoctoral Fellowship
- NCI Comprehensive Cancer Center [CA21765]
- American Lebanese Syrian Associated Charities (ALSAC)
- Patrick C. Walsh Fund
- Koch Fund
- NHLBI [HHSN-268201999934C]
- CIHR [20R92141]
- NIAID [F32 AI080086]
Ask authors/readers for more resources
Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4(+) and CD8(+) T cells in three distinct transplantable tumors. Dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3(-/-)Pdcd1(-/-) mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer. Cancer Res; 72(4); 917-27. (C) 2011 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available