2. Academic Validation
  3. Identification of VISTA regulators in macrophages mediating cancer cell survival

Identification of VISTA regulators in macrophages mediating cancer cell survival

  • Sci Adv. 2024 Nov 29;10(48):eadq8122. doi: 10.1126/sciadv.adq8122.
Abdalla M Abdrabou 1 2 3,  Sharif U Ahmed 4,  Mengqi Jonathan Fan 2,  Bill T V Duong 5,  Kangfu Chen 4,  Pei-Ying Lo 4,  Julia M Mayes 2,  Fatemeh Esmaeili 2 6,  Amin GhavamiNejad 4,  Hossein Zargartalebi 2 4,  Randy Singh Atwal 1,  Sichun Lin 7,  Stephane Angers 5 7 8,  Shana O Kelley 1 2 3 4 5 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 2 Department of Chemistry, Northwestern University, Evanston, IL, USA.
  • 3 Chan Zuckerberg Biohub Chicago, Chicago, IL, USA.
  • 4 Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.
  • 5 Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • 6 Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada.
  • 7 Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
  • 8 Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
PMID: 39602545 DOI: 10.1126/sciadv.adq8122
Abstract

Numerous human cancers have exhibited the ability to elude Immune Checkpoint blockade (ICB) therapies. This type of resistance can be mediated by immune-suppressive macrophages that limit antitumor immunity in the tumor microenvironment (TME). Here, we elucidate a strategy to shift macrophages into a proinflammatory state that down-regulates V domain immunoglobulin suppressor of T cell activation (VISTA) via inhibiting AhR and IRAK1. We used a high-throughput microfluidic platform combined with a genome-wide CRISPR knockout screen to identify regulators of VISTA levels. Functional characterization showed that the knockdown of these hits diminished VISTA surface levels on macrophages and sustained an antitumor phenotype. Furthermore, targeting of both AhR and IRAK1 in mouse models overcame resistance to ICB treatment. Tumor immunophenotyping indicated that infiltration of cytotoxic CD8+ cells, natural killer cells, and antitumor macrophages was substantially increased in treated mice. Collectively, AhR and IRAK1 are implicated as regulators of VISTA that coordinate a multifaceted barrier to antitumor immune responses.

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