Multimodal reprogramming of the tumor microenvironment by MMR and dual checkpoint blockade in hepatocellular carcinoma models

Authors

• Mulu Z. Tesfay, University of Arkansas for Medical Sciences, Little Rock, AR
• Aleksandra Cios, University of Arkansas for Medical Sciences, Little Rock, AR
• Khandoker Usran Ferdous, University of Arkansas for Medical Sciences, Little Rock, AR
• Randal S. Shelton, University of Arkansas for Medical Sciences, Little Rock, AR
• Bahaa Mustafa, University of Arkansas for Medical Sciences, Little Rock, AR
• Camila C. Simoes, University of Arkansas for Medical Sciences, Little Rock, AR
• Murat Gokden, University of Arkansas for Medical Sciences, Little Rock, AR
• Isabelle R. Miousse, University of Arkansas for Medical Sciences, Little Rock, AR
• Kimberly J. Krager, University of Arkansas for Medical Sciences, Little Rock, AR
• Marjan Boerma, University of Arkansas for Medical Sciences, Little Rock, AR
• Alicja Urbaniak, University of Arkansas for Medical Sciences, Little Rock, AR
• Anuradha Kunthur, University of Arkansas for Medical Sciences, Little Rock, AR
• Sri Obulareddy, University of Arkansas for Medical Sciences, Little Rock, AR
• Joshua M. Eichhorn, University of Arkansas for Medical Sciences, Little Rock, AR
• Steven R. Post, University of Arkansas for Medical Sciences, Little Rock, AR
• Jean Christopher Chamcheu, Louisiana State University, Baton Rouge, LA
• Omeed Moaven, LSU Health Sciences Center - New OrleansFollow
• Chiswili Y. Chabu, University of Missouri, Columbia, MO
• Dan G. Duda, Massachusetts General Hospital and Harvard Medical School, Boston, MA
• Matteo Conti, Azienda Unita' Sanitaria Locale Imola, Imola, Italy
• Bruno Nardo, University of Calabria, Rende, Italy
• Rang Govindarajan, University of Arkansas for Medical Sciences, Little Rock, AR
• Martin E. Fernandez-Zapico, Mayo Clinic, Rochester, MN
• Lewis R. Roberts, Mayo Clinic, Rochester, MN
• Mitesh J. Borad, Mayo Clinic, Phoenix, AZ
• Martin J. Cannon, University of Arkansas for Medical Sciences, Little Rock, AR
• Alexei G. Basnakian, University of Arkansas for Medical Sciences, Little Rock, AR
• Bolni M. Nagalo, University of Arkansas for Medical Sciences, Little Rock, AR

Document Type

Article

Publication Date

10-8-2025

Publication Title

Frontiers in Immunology

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, thus, there is an urgent need to develop more effective therapeutic options for this dismal condition. Tumor-infiltrating lymphocytes (TILs) are associated with improved response to immune checkpoint blockade in HCC, but their low abundance in most cases limits their therapeutic efficacy. Here, we demonstrate, in mice, that low-dose intratumoral immunovirotherapy with the trivalent measles, mumps, and rubella vaccine (MMR) induces superior tumor-growth delay and extended host survival compared to individually administered vaccines for measles, mumps, or rubella viruses. Further, our results show that MMR therapy synergizes with PD-1 and CTLA-4 blockade to reprogram the tumor microenvironment, resulting in increased CD8+ TIL infiltration and reduced PD-1 expression on TILs, among other effects. These changes in the immunological landscape translated into greater survival and more durable tumor-specific and memory immune responses for hosts. Comprehensive toxicology analysis revealed no evidence of MMR-induced liver or kidney toxicity after intrahepatic administration. This work reinforces an unrecognized role of MMR plus ICB in reprogramming the immune landscape in HCC through multimodal immune activation, providing a strong rationale for further development of MMR-based therapies for HCC.

First Page

1679665

PubMed ID

41142777

Volume

16

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Tesfay, Mulu Z.; Cios, Aleksandra; Ferdous, Khandoker Usran; Shelton, Randal S.; Mustafa, Bahaa; Simoes, Camila C.; Gokden, Murat; Miousse, Isabelle R.; Krager, Kimberly J.; Boerma, Marjan; Urbaniak, Alicja; Kunthur, Anuradha; Obulareddy, Sri; Eichhorn, Joshua M.; Post, Steven R.; Chamcheu, Jean Christopher; Moaven, Omeed; Chabu, Chiswili Y.; Duda, Dan G.; Conti, Matteo; Nardo, Bruno; Govindarajan, Rang; Fernandez-Zapico, Martin E.; Roberts, Lewis R.; Borad, Mitesh J.; Cannon, Martin J.; Basnakian, Alexei G.; and Nagalo, Bolni M., "Multimodal reprogramming of the tumor microenvironment by MMR and dual checkpoint blockade in hepatocellular carcinoma models" (2025). School of Graduate Studies Faculty Publications. 453.
https://digitalscholar.lsuhsc.edu/sogs_facpubs/453
10.3389/fimmu.2025.1679665