Immunosuppression limits effector CD8+ T cell entry into subcutaneous melanoma

Identification: 4061


Description

Immunosuppression limits effector CD8+ T cell entry into subcutaneous melanoma

Ashley L. Wilson1, Amber N. Woods1, Victor H. Engelhard1

1Beirne B. Carter Center for Immunology Research and Dept. of Microbiology, Immunology & Cancer Biology, Univ. of Virginia School of Medicine, Charlottesville, VA

Checkpoint blockade inhibition has emerged as a promising therapeutic strategy for many types of cancer. Despite achieving durable responses in a small number of patients, a vast majority fail to respond to treatment. Infiltration of effector CD8 T cells into tumors is associated with improved clinical response. Interactions between homing receptors (HR) and ligands on the vasculature facilitate CD8 T cell entry into tissues. HR ligand expression on normal inflamed tissue vasculature is induced by the local release of pro-inflammatory cytokines. In tumors, however, it is likely that expression of HR ligands on tumor vasculature is suboptimal due to immunosuppression. We hypothesized that disruption of immunosuppression would increase HR ligand expression on tumor vasculature, and consequently, enhance CD8 T cell entry. B16-F1 melanoma tumor-bearing mice were treated with a blocking antibody against CTLA-4, and HR ligand expression on tumor vasculature and CD8 T cell representation were assessed. We found that tumors responsive to CTLA-4 blockade had significantly increased CD8 T cell representation and reduced tumor burden. This subset of tumors also had increased VCAM-1 and intravascular CXCL9 expression. Increased VCAM-1, CXCL9, and CD8 T cell representation required IFNg signaling. While tumors responsive to CTLA-4 blockade had elevated numbers of cytokine-producing effectors, the frequency of intratumoral PD-1+ CD8 T cells significantly increased. Our data suggest that CTLA-4 blockade may act to enhance T cell activation in tumor-draining lymph nodes to increase the number of CD8 T cell effectors available to infiltrate tumors. It is also possible that CTLA-4 blockade may act on CTLA-4+ intratumoral Tregs, thereby promoting reactivation of tumor-resident CD8 T cell effectors that secrete pro-inflammatory cytokines that upregulate HR ligands on tumor vasculature.

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