Show simple item record

dc.contributor.authorSlovak, R.J.
dc.contributor.authorPark, H.-J.
dc.contributor.authorKamp, W.M.
dc.contributor.authorLudwig, J.M.
dc.contributor.authorKang, I.
dc.contributor.authorKim, H.S.
dc.date.accessioned2021-04-12T13:11:07Z
dc.date.available2021-04-12T13:11:07Z
dc.date.issued2021-03-26
dc.identifier.urihttp://hdl.handle.net/10713/15142
dc.description.abstractCheckpoint inhibitors have demonstrated clinical impact in colorectal cancer with deficient mismatch repair and high microsatellite instability. However, the majority of patients have disease with stable microsatellites that responds poorly to immunotherapies. Combinations of checkpoint inhibitors are under investigation as a way of increasing immunogenicity and promoting a robust anti-tumor immune response. The purpose of this study is to quantify the immune responses induced by mono and dual checkpoint inhibition in a mismatch repair proficient model of colorectal cancer (CRC). Tumor growth rates were monitored over time and compared between groups. We utilized fluorescence-activated cell sorting to analyze CD8+ and CD4+ T cells after treatment with either single PD-1 inhibition or dual PD-1 and CTLA-4 inhibition. Additionally, we sought to quantify the expression of co-inhibitory surface molecules PD-1, LAG3, and TIM3. Dual checkpoint inhibition was associated with a significantly slower growth rate as compared to either mono PD-1 inhibition or control (p < 0.05). Neither monotherapy nor dual checkpoint inhibition significantly affected the tumoral infiltration of lymphocytes. After treatment with dual inhibitors, infiltrating CD8+ T cells demonstrated significantly less expression of PD-1 (1700 vs. 2545 and 2462; p < 0.05) and LAG3 (446.2 vs. 694.4 and 707; p < 0.05) along with significantly more expression of TIM3 (12,611 vs. 2961 and 4259; p < 0.05) versus the control and anti-PD-1 groups. These results suggest that dual therapy with anti-CTLA-4 and anti-PD-1 antibodies significantly inhibits growth of microsatellite stable CRC by suppressing immunosuppressive checkpoints. Upregulation of TIM3 represents a potential escape mechanism and a target for future combination immunotherapies in CRC. Copyright 2021, The Author(s).en_US
dc.description.sponsorshipThis study was supported by the United States Department of Defense (CA160741).en_US
dc.description.urihttps://doi.org/10.1038/s41598-021-85810-5en_US
dc.language.isoen_USen_US
dc.publisherNature Researchen_US
dc.relation.ispartofScientific Reports
dc.subject.meshImmune Checkpoint Inhibitorsen_US
dc.subject.meshColorectal Neoplasmsen_US
dc.titleCo-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal canceren_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41598-021-85810-5
dc.identifier.pmid33772035


This item appears in the following Collection(s)

Show simple item record