Loss of PARP7 increases type I interferon signalling and prevents pancreatic tumour growth by enhancing immune cell infiltration

Kannen, V.; Rasmussen, M.; Das, S.; Giuliana, P.; Izzati, F. N.; Choksi, H.; Erlingsson, L. A. M.; Olafsen, N. E.; Cappello, P.; Teino, I.; Maimets, T.; Jaudzems, K.; Gulbinas, A.; Dambrauskas, Z.; Edgar, L. J.; Grant, D. M.; Matthews, J.

doi:10.1101/2024.09.18.613621

bioRxiv · 10.1101/2024.09.18.613621

Loss of PARP7 increases type I interferon signalling and prevents pancreatic tumour growth by enhancing immune cell infiltration

Kannen, V.·Rasmussen, M.·Das, S.·Giuliana, P.·Izzati, F. N.·Choksi, H.·Erlingsson, L. A. M.·Olafsen, N. E.·Cappello, P.·Teino, I.·Maimets, T.·Jaudzems, K.·Gulbinas, A.·Dambrauskas, Z.·Edgar, L. J.·Grant, D. M.·Matthews, J.

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and despite low incidence rates, it remains the sixth leading cause of cancer related deaths worldwide. Immunotherapy, which aims to enhance the immune systems ability to recognize and eliminate cancer cells, has emerged as a promising approach in the battle against PDAC. PARP7, a mono-ADP-ribosyltransferase, is a negative regulator of the type I interferon (IFN-I) pathway and has been reported to reduce anti-tumour immunity. Using murine pancreatic cancer cells, we found that loss of Parp7 elevated the levels of interferon stimulated gene factor 3 (ISGF3) and its downstream target genes, even in the absence of STING. Cancer cells deficient in Parp7 produced smaller tumours when injected into immunocompetent mice. Transcriptomic analyses revealed that tumours knocked out for Parp7 (Parp7KO) had increased expression of genes involved in immunoregulatory interactions and interferon signalling pathways. Characterization of tumour infiltrating leukocyte (TIL) populations showed that Parp7KO tumours had higher proportions of natural killer cells, CD8 T cells and a lower proportion of anti-inflammatory macrophages (M2). The overall TIL profile of Parp7KO tumours was suggestive of a less suppressive microenvironment. Our data show that loss of Parp7 reduces PDAC tumour growth by increasing the infiltration of immune cells and enhancing anti-tumour immunity. These findings provide support to pursue PARP7 as a therapeutic target for PDAC.

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Kannen, V., Rasmussen, M., Das, S., Giuliana, P., Izzati, F. N., Choksi, H., Erlingsson, L. A. M., Olafsen, N. E., Cappello, P., Teino, I., Maimets, T., Jaudzems, K., Gulbinas, A., Dambrauskas, Z., Edgar, L. J., Grant, D. M., Matthews, J.. 2024-09-22. Loss of PARP7 increases type I interferon signalling and prevents pancreatic tumour growth by enhancing immune cell infiltration. https://doi.org/10.1101/2024.09.18.613621

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