Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance

Tommaso Scolaro; Marta Manco; Mathieu Pecqueux; Ricardo Amorim; Rosa Trotta; Heleen H. Van Acker; Matthias Van Haele; Niranjan Shirgaonkar; Stefan Naulaerts; Jan Daniluk; Fran Prenen; Chiara Varamo; Donatella Ponti; Ginevra Doglioni; Ana Margarida Ferreira Campos; Juan Fernandez Garcia; Silvia Radenkovic; Pegah Rouhi; Aleksandar Beatovic; Liwei Wang; Yu Wang; Amalia Tzoumpa; Asier Antoranz; Ara Sargsian; Mario Di Matteo; Emanuele Berardi; Jermaine Goveia; Bart Ghesquière; Tania Roskams; Stefaan Soenen; Thomas Voets; Bella Manshian; Sarah Maria Fendt; Peter Carmeliet; Abhishek D. Garg; Ramanuj DasGupta; Baki Topal; Massimiliano Mazzone

doi:10.1038/s43018-024-00771-8

Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance

Tommaso Scolaro, Marta Manco, Mathieu Pecqueux, Ricardo Amorim, Rosa Trotta, Heleen H. Van Acker, Matthias Van Haele, Niranjan Shirgaonkar, Stefan Naulaerts, Jan Daniluk, Fran Prenen, Chiara Varamo, Donatella Ponti, Ginevra Doglioni, Ana Margarida Ferreira Campos, Juan Fernandez Garcia, Silvia Radenkovic, Pegah Rouhi, Aleksandar Beatovic, Liwei WangYu Wang, Amalia Tzoumpa, Asier Antoranz, Ara Sargsian, Mario Di Matteo, Emanuele Berardi, Jermaine Goveia, Bart Ghesquière, Tania Roskams, Stefaan Soenen, Thomas Voets, Bella Manshian, Sarah Maria Fendt, Peter Carmeliet, Abhishek D. Garg, Ramanuj DasGupta, Baki Topal, Massimiliano Mazzone^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y₆. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y₆ in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDA^high cancer cells match with T cell cytotoxicity dysfunction and P2RY6^high TAMs. Overall, we suggest CDA and P2Y₆ as potential targets for cancer immunotherapy.

Original language	English
Pages (from-to)	1206-1226
Number of pages	21
Journal	Nature Cancer
Volume	5
Issue number	8
DOIs	https://doi.org/10.1038/s43018-024-00771-8
Publication status	Published - Aug 2024
Externally published	Yes

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Scolaro, T., Manco, M., Pecqueux, M., Amorim, R., Trotta, R., Van Acker, H. H., Van Haele, M., Shirgaonkar, N., Naulaerts, S., Daniluk, J., Prenen, F., Varamo, C., Ponti, D., Doglioni, G., Ferreira Campos, A. M., Fernandez Garcia, J., Radenkovic, S., Rouhi, P., Beatovic, A., ... Mazzone, M. (2024). Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance. Nature Cancer, 5(8), 1206-1226. https://doi.org/10.1038/s43018-024-00771-8

@article{952e7c296bc748c6963eb7211853fe58,

title = "Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance",

abstract = "Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y6. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y6 in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDAhigh cancer cells match with T cell cytotoxicity dysfunction and P2RY6high TAMs. Overall, we suggest CDA and P2Y6 as potential targets for cancer immunotherapy.",

author = "Tommaso Scolaro and Marta Manco and Mathieu Pecqueux and Ricardo Amorim and Rosa Trotta and {Van Acker}, {Heleen H.} and {Van Haele}, Matthias and Niranjan Shirgaonkar and Stefan Naulaerts and Jan Daniluk and Fran Prenen and Chiara Varamo and Donatella Ponti and Ginevra Doglioni and {Ferreira Campos}, {Ana Margarida} and {Fernandez Garcia}, Juan and Silvia Radenkovic and Pegah Rouhi and Aleksandar Beatovic and Liwei Wang and Yu Wang and Amalia Tzoumpa and Asier Antoranz and Ara Sargsian and {Di Matteo}, Mario and Emanuele Berardi and Jermaine Goveia and Bart Ghesqui{\`e}re and Tania Roskams and Stefaan Soenen and Thomas Voets and Bella Manshian and Fendt, {Sarah Maria} and Peter Carmeliet and Garg, {Abhishek D.} and Ramanuj DasGupta and Baki Topal and Massimiliano Mazzone",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = aug,

doi = "10.1038/s43018-024-00771-8",

language = "English",

volume = "5",

pages = "1206--1226",

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Scolaro, T, Manco, M, Pecqueux, M, Amorim, R, Trotta, R, Van Acker, HH, Van Haele, M, Shirgaonkar, N, Naulaerts, S, Daniluk, J, Prenen, F, Varamo, C, Ponti, D, Doglioni, G, Ferreira Campos, AM, Fernandez Garcia, J, Radenkovic, S, Rouhi, P, Beatovic, A, Wang, L, Wang, Y, Tzoumpa, A, Antoranz, A, Sargsian, A, Di Matteo, M, Berardi, E, Goveia, J, Ghesquière, B, Roskams, T, Soenen, S, Voets, T, Manshian, B, Fendt, SM, Carmeliet, P, Garg, AD, DasGupta, R, Topal, B & Mazzone, M 2024, 'Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance', Nature Cancer, vol. 5, no. 8, pp. 1206-1226. https://doi.org/10.1038/s43018-024-00771-8

TY - JOUR

T1 - Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance

AU - Scolaro, Tommaso

AU - Manco, Marta

AU - Pecqueux, Mathieu

AU - Amorim, Ricardo

AU - Trotta, Rosa

AU - Van Acker, Heleen H.

AU - Van Haele, Matthias

AU - Shirgaonkar, Niranjan

AU - Naulaerts, Stefan

AU - Daniluk, Jan

AU - Prenen, Fran

AU - Varamo, Chiara

AU - Ponti, Donatella

AU - Doglioni, Ginevra

AU - Ferreira Campos, Ana Margarida

AU - Fernandez Garcia, Juan

AU - Radenkovic, Silvia

AU - Rouhi, Pegah

AU - Beatovic, Aleksandar

AU - Wang, Liwei

AU - Wang, Yu

AU - Tzoumpa, Amalia

AU - Antoranz, Asier

AU - Sargsian, Ara

AU - Di Matteo, Mario

AU - Berardi, Emanuele

AU - Goveia, Jermaine

AU - Ghesquière, Bart

AU - Roskams, Tania

AU - Soenen, Stefaan

AU - Voets, Thomas

AU - Manshian, Bella

AU - Fendt, Sarah Maria

AU - Carmeliet, Peter

AU - Garg, Abhishek D.

AU - DasGupta, Ramanuj

AU - Topal, Baki

AU - Mazzone, Massimiliano

PY - 2024/8

Y1 - 2024/8

N2 - Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y6. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y6 in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDAhigh cancer cells match with T cell cytotoxicity dysfunction and P2RY6high TAMs. Overall, we suggest CDA and P2Y6 as potential targets for cancer immunotherapy.

AB - Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y6. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y6 in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDAhigh cancer cells match with T cell cytotoxicity dysfunction and P2RY6high TAMs. Overall, we suggest CDA and P2Y6 as potential targets for cancer immunotherapy.

UR - http://www.scopus.com/inward/record.url?scp=85195310685&partnerID=8YFLogxK

U2 - 10.1038/s43018-024-00771-8

DO - 10.1038/s43018-024-00771-8

M3 - Article

C2 - 38844817

AN - SCOPUS:85195310685

VL - 5

SP - 1206

EP - 1226

JO - Nature Cancer

JF - Nature Cancer

IS - 8

ER -

Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance

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