Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Enhancement of Adiation Therapy through Blockade of the Immune Checkpoint VISTA in Melanoma and Adenocarcinoma Murine Models

Kayla E.A. Duval
,
Armin D. Tavakkoli
ORCID logo ,
Alireza Kheirollah
,
Haille E. Soderholm
,
Eugene Demidenko
,
Janet L. Lines
,
Walburga Croteau
,
Robert J. Wagner
,
Ethan Aulwes
,
Randolph J. Noelle
,
P. Jack Hoopes
*
Version 1 : Received: 29 August 2023 / Approved: 30 August 2023 / Online: 1 September 2023 (13:32:50 CEST)

A peer-reviewed article of this Preprint also exists.

Duval, K.E.A.; Tavakkoli, A.D.; Kheirollah, A.; Soderholm, H.E.; Demidenko, E.; Lines, J.L.; Croteau, W.; Zhang, S.C.; Wagner, R.J.; Aulwes, E.; Noelle, R.J.; Hoopes, P.J. Enhancement of Radiation Therapy through Blockade of the Immune Checkpoint, V-domain Ig Suppressor of T Cell Activation (VISTA), in Melanoma and Adenocarcinoma Murine Models. Int. J. Mol. Sci. 2023, 24, 13742. Duval, K.E.A.; Tavakkoli, A.D.; Kheirollah, A.; Soderholm, H.E.; Demidenko, E.; Lines, J.L.; Croteau, W.; Zhang, S.C.; Wagner, R.J.; Aulwes, E.; Noelle, R.J.; Hoopes, P.J. Enhancement of Radiation Therapy through Blockade of the Immune Checkpoint, V-domain Ig Suppressor of T Cell Activation (VISTA), in Melanoma and Adenocarcinoma Murine Models. Int. J. Mol. Sci. 2023, 24, 13742.

Abstract

Introduction: Radiation therapy (RT) has recently demonstrated promise at stimulating an enhanced immune response. The recent success of immunotherapies, such as checkpoint inhibitors, CART cells, and other immune modulators, affords new opportunities for combination with radiation. Methods: In this study, VISTA, an immune checkpoint, was blocked either by genetic knockout (KO) or an inhibitory antibody and combined with RT in two syngeneic murine cancer models. Selected mRNA, immune cell infiltration, and tumor growth delay were used to assess the biological effects. Results: When combined with a single 15 Gy radiation doses, both VISTA blockade techniques significantly enhanced anti-tumor immune signaling pathways at the mRNA, cellular infiltration level and tumor growth delay. The data suggests that the mechanism behind the enhanced tumor control is primarily a result of increased apoptosis and immune mediated cytotoxicity. Conclusion: VISTA blockade significantly enhances the anti-tumor effect of a single dose of 15 Gy radiation through increased expression and stimulation of cell mediated apoptosis pathways. These results suggest that VISTA is a biologically relevant immune promoter that has the potential to enhance the efficacy of a large single radiation dose in a synergic manner.

Keywords

Checkpoint Inhibitor; VISTA; Radiation therapy

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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