American Association for Cancer Research
00085472can190086-sup-214986_2_supp_5633057_pdc4xj.pdf (1.45 MB)

Figures S1-S4 from Inactivation of Proprotein Convertases in T Cells Inhibits PD-1 Expression and Creates a Favorable Immune Microenvironment in Colorectal Cancer

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journal contribution
posted on 2023-03-31, 02:41 authored by Mercedes Tomé, Angela Pappalardo, Fabienne Soulet, José Javier López, Jone Olaizola, Yannick Leger, Marielle Dubreuil, Amandine Mouchard, Delphine Fessart, Frédéric Delom, Vincent Pitard, Dominique Bechade, Mariane Fonck, Juan Antonio Rosado, François Ghiringhelli, Julie Déchanet-Merville, Isabelle Soubeyran, Geraldine Siegfried, Serge Evrard, Abdel-Majid Khatib

PCs expression in T cells and effect of PC inhibition on PD-1 expression, T cell signaling, survival and cytotoxicity.






Proprotein convertases (PC) activate precursor proteins that play crucial roles in various cancers. In this study, we investigated whether PC enzyme activity is required for expression of the checkpoint protein programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTL) in colon cancer. Although altered expression of the PC secretory pathway was observed in human colon cancers, only furin showed highly diffuse expression throughout the tumors. Inhibition of PCs in T cells using the general protein-based inhibitor α1-PDX or the pharmacologic inhibitor Decanoyl-Arg-Val-Lys-Arg-chloromethylketone repressed PD-1 and exhausted CTLs via induction of T-cell proliferation and apoptosis inhibition, which improved CTL efficacy against microsatellite instable and microsatellite stable colon cancer cells. In vivo, inhibition of PCs enhanced CTL infiltration in colorectal tumors and increased tumor clearance in syngeneic mice compared with immunodeficient mice. Inhibition of PCs repressed PD-1 expression by blocking proteolytic maturation of the Notch precursor, inhibiting calcium/NFAT and NF-κB signaling, and enhancing ERK activation. These findings define a key role for PCs in regulating PD-1 expression and suggest targeting PCs as an adjunct approach to colorectal tumor immunotherapy. Protein convertase enzymatic activity is required for PD-1 expression on T cells, and inhibition of protein convertase improves T-cell targeting of microsatellite instable and stable colorectal cancer.