Fc-optimized anti-CTLA-4 antibodies increase tumor-associated high endothelial venules and sensitize refractory tumors to PD-1 blockade Journal Article
| Authors: | Blanchard, L.; Vina, E.; Ljubetic, J.; Meneur, C.; Tarroux, D.; Baez, M.; Marino, A.; Ortega, N.; Knorr, D. A.; Ravetch, J. V.; Girard, J. P. |
| Article Title: | Fc-optimized anti-CTLA-4 antibodies increase tumor-associated high endothelial venules and sensitize refractory tumors to PD-1 blockade |
| 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 remodelers 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. © 2025 The Author(s) |
| Keywords: | controlled study; unclassified drug; nonhuman; flow cytometry; antineoplastic agent; cd8+ t lymphocyte; animal cell; mouse; animal tissue; gene; cytotoxic t lymphocyte antigen 4 antibody; ipilimumab; cancer immunotherapy; gene expression; cell infiltration; tumor volume; animal experiment; animal model; immunofluorescence; genetic transfection; gamma interferon; immunoglobulin g; cd4+ t lymphocyte; blood vessel; fc receptor; ctla-4; lymphocyte; interleukin 2 receptor alpha; antibody engineering; programmed death 1 receptor; padgem protein; tumor-infiltrating lymphocytes; lymphocyte trafficking; tumor microenvironment; peptides and proteins; fc receptors; icos gene; fluorescence intensity; 3 methylcholanthrene; female; article; immunofluorescence assay; fibrosarcoma cell line; pd-1 blockade; foxp3 gene; ifngr1 gene; receptor type tyrosine protein phosphatase c; platelet endothelial cell adhesion molecule 1; b16-f10 cell line; refractory tumor; checkpoint inhibitor therapy; cell line by cell type; high endothelial venule; tumor blood vessels; antibodies,antisera and immunoglobulins; meca-79 protein; pd-1 antibodies; antibody and immunoglobulin structure; cd39 gene; ctla-4 gene; expi293f cell line; fc domain; fcgr1a gene; fcgr2b gene; fcgr3 gene; fcgr4 gene; gzmb gene; ifngr2 gene; mca-205 fibrosarcoma cell; pd-1 gene; slamf6 gene; tbet gene; tim3 gene; tumor-associated high endothelial venules |
| Journal Title: | Cell Reports Medicine |
| Volume: | 6 |
| Issue: | 6 |
| ISSN: | 2666-3791 |
| Publisher: | Cell Press |
| Date Published: | 2025-06-17 |
| Start Page: | 102141 |
| Language: | English |
| DOI: | 10.1016/j.xcrm.2025.102141 |
| PUBMED: | 40460830 |
| PROVIDER: | scopus |
| PMCID: | PMC12208319 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
