Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice

Benjamin Assouline; Rachel Kahn; Lutfi Hodali; Reba Condiotti; Yarden Engel; Ela Elyada; Tzlil Mordechai-Heyn; Jason R. Pitarresi; Dikla Atias; Eliana Steinberg; Tirza Bidany-Mizrahi; Esther Forkosh; Lior H. Katz; Ofra Benny; Talia Golan; Matan Hofree; Sheila A. Stewart; Karine A. Atlan; Gideon Zamir; Ben Z. Stanger; Michael Berger; Ittai Ben-Porath

doi:10.1038/s41467-024-50441-7

Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8⁺ T cell activation and limit responsiveness to immunotherapy in mice

Benjamin Assouline, Rachel Kahn, Lutfi Hodali, Reba Condiotti, Yarden Engel, Ela Elyada, Tzlil Mordechai-Heyn, Jason R. Pitarresi, Dikla Atias, Eliana Steinberg, Tirza Bidany-Mizrahi, Esther Forkosh, Lior H. Katz, Ofra Benny, Talia Golan, Matan Hofree, Sheila A. Stewart, Karine A. Atlan, Gideon Zamir, Ben Z. StangerMichael Berger, Ittai Ben-Porath^*

^*Corresponding author for this work

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

3 Scopus citations

Abstract

Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8⁺ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8⁺ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.

Original language	English
Article number	6162
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-50441-7
State	Published - Dec 2024

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Publisher Copyright:
© The Author(s) 2024.

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Cite this

Assouline, B., Kahn, R., Hodali, L., Condiotti, R., Engel, Y., Elyada, E., Mordechai-Heyn, T., Pitarresi, J. R., Atias, D., Steinberg, E., Bidany-Mizrahi, T., Forkosh, E., Katz, L. H., Benny, O., Golan, T., Hofree, M., Stewart, S. A., Atlan, K. A., Zamir, G., ... Ben-Porath, I. (2024). Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8⁺ T cell activation and limit responsiveness to immunotherapy in mice. Nature Communications, 15(1), Article 6162. https://doi.org/10.1038/s41467-024-50441-7

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title = "Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice",

abstract = "Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.",

author = "Benjamin Assouline and Rachel Kahn and Lutfi Hodali and Reba Condiotti and Yarden Engel and Ela Elyada and Tzlil Mordechai-Heyn and Pitarresi, {Jason R.} and Dikla Atias and Eliana Steinberg and Tirza Bidany-Mizrahi and Esther Forkosh and Katz, {Lior H.} and Ofra Benny and Talia Golan and Matan Hofree and Stewart, {Sheila A.} and Atlan, {Karine A.} and Gideon Zamir and Stanger, {Ben Z.} and Michael Berger and Ittai Ben-Porath",

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Assouline, B, Kahn, R, Hodali, L, Condiotti, R, Engel, Y, Elyada, E, Mordechai-Heyn, T, Pitarresi, JR, Atias, D, Steinberg, E, Bidany-Mizrahi, T, Forkosh, E, Katz, LH, Benny, O, Golan, T, Hofree, M, Stewart, SA, Atlan, KA, Zamir, G, Stanger, BZ, Berger, M & Ben-Porath, I 2024, 'Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8⁺ T cell activation and limit responsiveness to immunotherapy in mice', Nature Communications, vol. 15, no. 1, 6162. https://doi.org/10.1038/s41467-024-50441-7

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AU - Assouline, Benjamin

AU - Kahn, Rachel

AU - Hodali, Lutfi

AU - Condiotti, Reba

AU - Engel, Yarden

AU - Elyada, Ela

AU - Mordechai-Heyn, Tzlil

AU - Pitarresi, Jason R.

AU - Atias, Dikla

AU - Steinberg, Eliana

AU - Bidany-Mizrahi, Tirza

AU - Forkosh, Esther

AU - Katz, Lior H.

AU - Benny, Ofra

AU - Golan, Talia

AU - Hofree, Matan

AU - Stewart, Sheila A.

AU - Atlan, Karine A.

AU - Zamir, Gideon

AU - Stanger, Ben Z.

AU - Berger, Michael

AU - Ben-Porath, Ittai

PY - 2024/12

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N2 - Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.

AB - Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.

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