Inhibition of SHP-1 expands the repertoire of anti-tumor T cells available to respond to checkpoint blockade therapy

Abstract

Abstract The presence and activity of CD8+T cells within the tumor microenvironment is essential for the control of tumor growth and impediment of cancer progression. Utilizing B16 F10 melanoma tumors that express altered peptide ligands of OVA257–264, we measured high- and low-affinity OVA-specific responses following adoptive transfer of OT-1 CD8+T cell into tumor-bearing mice. As expected, we found that TCR affinity positively correlated with the frequency of OT-1 tumor infiltrating lymphocytes (TILs). The differences in TCR affinity inversely corresponded to in vivo tumor growth rate. We next sought to determine whether checkpoint blockade therapy (CB: anti-PD-1; anti-CTLA-4) could enhance the recruitment of low affinity T cells. However, CB only increased the frequency of OT-1 TILs responding to high affinity antigens, while failing to alter the response or protective capacity of intermediate to low affinity T cell responses. To explore whether lowering TCR activation threshold could enhance the breadth and magnitude of the anti-tumor T cell response, we used shRNA to knock down Src homology region 2 domain-containing phosphatase 1 (SHP-1) in OT-1 T cells prior to tumor antigen exposure. Unlike CB, SHP-1 knockdown increased the magnitude and effector function of both low affinity and high affinity OT-1 T cells. When SHP-1 knockdown was combined with immunotherapy, we observed an additional boost in the OT-1 response, as well as enhanced tumor control by intermediate to low-affinity OT-1s. We conclude that targeting TCR activation threshold expands the repertoire of T cells available to respond to conventional CB, leading to enhanced control of tumor growth.