VISTA immune checkpoint blunts radiotherapy-induced antitumor immune response
Radiotherapy (RT) is a key treatment for solid neoplasms like head and neck cancer (HNC), but it can also activate and recruit immunosuppressive myeloid cells, causing treatment failure. In this study, we examine the role of V-domain immunoglobulin suppressor of T cell activation (VISTA) on myeloid cells during RT. We discovered high VISTA expression on myeloid cells in the tumor microenvironment (TME) of both murine and human HNC, with RT increasing VISTA<sup>+</sup> myeloid cells in the TME and circulation. Compared to VISTA<sup>+/+</sup> mice, VISTA<sup>-/-</sup> mice showed improved tumor control with RT, with their macrophages and neutrophils exhibiting antitumorigenic properties on sc-RNA-seq analysis, especially with RT. Combining anti-VISTA antibodies (active or silent Fc) with RT (fractionated or ablative) significantly decreased tumor volume compared to either treatment alone in multiple preclinical models (HNC, breast cancer, and colorectal cancer), enhancing systemic antitumor immune response with augmented intra-tumoral T cell function through myeloid repolarization. Targeting VISTA could improve the efficacy of RT.
Authors
- Quynh‐Thu Le (ORCID: https://orcid.org/0000-0002-3682-1439)
- Vasu Divi (ORCID: https://orcid.org/0000-0002-6219-6294)
- Bhushan Dharmadhikari (ORCID: https://orcid.org/0000-0003-1626-5639)
- Sainiteesh Maddineni (ORCID: https://orcid.org/0000-0003-4152-273X)
- Dhanya K. Nambiar (ORCID: https://orcid.org/0000-0002-0648-403X)
- Nishant Mehta (ORCID: https://orcid.org/0000-0002-7920-609X)
- John B. Sunwoo (ORCID: https://orcid.org/0000-0002-8393-4196)
- Dipti Thakkar (ORCID: https://orcid.org/0009-0004-9947-3779)
- Alexander M. Real
- Jimpi Langthasa (ORCID: https://orcid.org/0000-0002-7675-2458)
- Andrey Finegersh (ORCID: https://orcid.org/0000-0002-2639-2132)
- John Aleman (ORCID: https://orcid.org/0000-0002-1691-6262)
- Jennifer R. Cochran (ORCID: https://orcid.org/0000-0002-6532-9873)
- Tia Cheunkarndee
- Md Tauhidul Islam (ORCID: https://orcid.org/0000-0001-6259-632X)
- Vignesh Viswanathan (ORCID: https://orcid.org/0000-0001-8307-9508)
- Christina S. Kong
- J. Howard Frank
- Jerome D. Boyd‐Kirkup (ORCID: https://orcid.org/0000-0002-6033-2619)
- Hongbin Cao (ORCID: https://orcid.org/0000-0001-8596-3268)
- Eyiwunmi E. Laseinde
- Lei Xing (ORCID: https://orcid.org/0000-0003-2536-5359)
- Junyan Liu (ORCID: https://orcid.org/0009-0004-9048-9088)
- Xiao‐Jing Wang (ORCID: https://orcid.org/0000-0003-3124-8474)
Institutions
- Stanford Medicine (US)
- VA Northern California Health Care System (US)
- University of California Davis Medical Center (US)
- University of Colorado Anschutz Medical Campus (US)
- Stanford University (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1016/j.celrep.2025.115893
- Citations
- 1
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health
- School of Medicine, Stanford University
- National Cancer Institute
- National Institute of Dental and Craniofacial Research