Blanchard and Vina et al. investigated mechanisms by which anti-CTLA-4 mAbs modulate tumor-associated high endothelial venules (TA-HEVs), which are important for supporting lymphocyte entry into tumors. In mouse models, anti-CTLA-4 Fc-derived effector function was required to increase TA-HEVs. CD4+ T cells and IFNγ were also found to be important during anti-CTLA-4 therapy. Consequently, Fc engineering of ipilimumab was necessary to increase TA-HEVs in humanized mice. Combination with anti-PD-1 increased TA-HEVs, promoted CD4+ and CD8+ T cell infiltration into tumors, and sensitized cold, refractory tumors to PD-1 blockade.

Contributed by Katherine Turner

ABSTRACT: The lack of T cells in tumors is a major hurdle to successful immune checkpoint therapy (ICT). Therefore, therapeutic strategies promoting T cell recruitment into tumors are warranted to improve the treatment efficacy. Here, we report that Fc-optimized anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies are potent re-modelers of tumor vasculature that increase tumor-associated high endothelial venules (TA-HEVs), specialized blood vessels supporting lymphocyte entry into tumors. Mechanistically, this effect is dependent on the Fc domain of anti-CTLA-4 antibodies and CD4+ T cells and involves interferon gamma (IFNγ). Unexpectedly, we find that the human anti-CTLA-4 antibody ipilimumab fails to increase TA-HEVs in a humanized mouse model. However, increasing its Fc effector function rescues the modulation of TA-HEVs, promotes CD4+ and CD8+ T cell infiltration into tumors, and sensitizes recalcitrant tumors to programmed cell death protein 1 (PD-1) blockade. Our findings suggest that Fc-optimized anti-CTLA-4 antibodies could be used to reprogram tumor vasculature in poorly immunogenic cold tumors and improve the efficacy of ICT.

Author Info: 1-Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France 2-Equipe Labellisée LIGUE 2023, Paris, France 3-Laboratory of Mo

Author Info: 1-Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France 2-Equipe Labellisée LIGUE 2023, Paris, France 3-Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY, USA 4-Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5-These authors contributed equally 6-Lead contact *Correspondence: lblanchard@rockefeller.edu, jean-philippe.girard@ipbs.fr