VISTA immune checkpoint blunts radiotherapy-induced antitumor immune response

Dhanya K Nambiar¹, Sainiteesh Maddineni², Jimpi Langthasa³, Hongbin Cao³, Vignesh Viswanathan³, Junyan Liu³, Md Tauhidul Islam³, Nishant Mehta⁴, Jessica Frank⁴, Alexander Real⁴, Tia Cheunkarndee³, Eyiwunmi Eghonghon Laseinde³, Bhushan Dharmadhikari⁵, Dipti Thakkar⁵, Jerome D Boyd-Kirkup⁵, Andrey Finegersh², Vasu Divi², John B Sunwoo², John Aleman⁶, Xiao-Jing Wang⁷, Christina Kong⁸, Lei Xing³, Jennifer R Cochran⁴, Quynh-Thu Le⁹

Affiliations

¹ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: dknambiar12@gmail.com.
² Department of Otolaryngology, Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA.
³ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Bioengineering, Stanford University Schools of Engineering and Medicine, Stanford, CA, USA.
⁵ Hummingbird Bioscience, Singapore, Singapore.
⁶ Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
⁷ Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Department of Pathology and Laboratory Medicine, University of California, Davis, School of Medicine, Davis, CA, USA; VA Northern California Health Care System, Sacramento, CA, USA.
⁸ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: qle@stanford.edu.

PMID: 40580480
DOI: 10.1016/j.celrep.2025.115893

Free article

VISTA immune checkpoint blunts radiotherapy-induced antitumor immune response

Dhanya K Nambiar et al. Cell Rep. 2025.

Free article

. 2025 Jul 22;44(7):115893.

doi: 10.1016/j.celrep.2025.115893. Epub 2025 Jun 27.

Authors

Affiliations

¹ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: dknambiar12@gmail.com.
² Department of Otolaryngology, Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA.
³ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Bioengineering, Stanford University Schools of Engineering and Medicine, Stanford, CA, USA.
⁵ Hummingbird Bioscience, Singapore, Singapore.
⁶ Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
⁷ Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; Department of Pathology and Laboratory Medicine, University of California, Davis, School of Medicine, Davis, CA, USA; VA Northern California Health Care System, Sacramento, CA, USA.
⁸ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: qle@stanford.edu.

PMID: 40580480
DOI: 10.1016/j.celrep.2025.115893

Abstract

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⁺ myeloid cells in the TME and circulation. Compared to VISTA^+/+ mice, VISTA^-/- 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.

Keywords: CP: Cancer; CP: Immunology; HNSCC; MDSC; VISTA; antitumor immune response; immune checkpoint; radiotherapy.

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Conflict of interest statement

Declaration of interests J.R.C. is a cofounder and equity holder of Combangio, Inc. (now Kala Bio), xCella Biosciences (now OmniAb), TwoStep Therapeutics, and Red Tree Venture Capital, and is a member of the Board of Directors of OmniAb, Revel Pharmaceuticals, Kivu Bioscience, Rondo Therapeutics, and Biograph 55, and is a Board Observer at Excellergy Therapeutics and Ebvio.

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VISTA immune checkpoint blunts radiotherapy-induced antitumor immune response

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VISTA immune checkpoint blunts radiotherapy-induced antitumor immune response

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