Is Vista: VSIG3 an Actionable Immune Checkpoint Target in Kidney Cancer?
Abstract
Hypothesis: The failure of PD-1 blockade in RCC is due to activation of other immune checkpoint pathways, such as VISTA, which may be targeted for greater therapeutic benefit in cancers refractory to PD-1 pathway blockade. Specific Aims: (1) Determine whether blocking the VISTA immune checkpoint pathway improves the response to PD-1 pathway blockade in the RENCA model. (2) Determine which cell types in human RCC express VISTA, VSIG3, VSIG8 and PSGL-1. Major Findings: We have developed VISTA and VSIG3 antibodies to test for blocking ability in in vitro functional assay and the RENCA mouse model. However in neutral conditions, I was able to reproduce VSIG3 binding with VISTA, but not the binding of VSIG8 with VISTA. Others have reported the the acidic environment of a tumor may change the charge of residues within the histidine-rich extracellular domain of VISTA in vivo, thus improving the specificity of clinically relevant binding partners, such as PSGL-1. I have reproduced the human PSGL1:human VISTA binding in vitro, but this does not appear to be conserved with mouse PSGL-1:mouse VISTA in vitro. We have explored the blocking antibodies that would block both VSIG3 and PSGL-1 binding with VISTA and the lead antibody failed to improve outcomes alone or in combination with PD-1 blockade in the RENCA tumor. Our data suggested that PSGL1:VISTA make be a critical pathway in the immune suppressive environment of the human tumor, but may not be testable in syngenetic mouse models.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2021
- Accession Number
- AD1172215
Entities
People
- Kathleen M Mahoney
Organizations
- Dana–Farber Cancer Institute