Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD

Chi Ma; Qiong Fu; Laurence P. Diggs; John C. McVey; Justin McCallen; Simon Wabitsch; Benjamin Ruf; Zachary Brown; Bernd Heinrich; Qianfei Zhang; Umberto Rosato; Sophie Wang; Linda Cui; Jay A. Berzofsky; David E. Kleiner; Dale B. Bosco; Long Jun Wu; Chunwei Walter Lai; Yaron Rotman; Changqing Xie; Firouzeh Korangy; Tim F. Greten

doi:10.1016/j.ccell.2022.08.004

Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD

Chi Ma, Qiong Fu, Laurence P. Diggs, John C. McVey, Justin McCallen, Simon Wabitsch, Benjamin Ruf, Zachary Brown, Bernd Heinrich, Qianfei Zhang, Umberto Rosato, Sophie Wang, Linda Cui, Jay A. Berzofsky, David E. Kleiner, Dale B. Bosco, Long Jun Wu, Chunwei Walter Lai, Yaron Rotman, Changqing XieFirouzeh Korangy, Tim F. Greten

Neurology

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

Abstract

Platelets, the often-overlooked component of the immune system, have been shown to promote tumor growth. Non-alcoholic fatty liver disease (NAFLD) is a common disease in the Western world and rising risk for hepatocellular carcinoma (HCC). Unexpectedly, we observed that platelets can inhibit the growth of established HCC in NAFLD mice. Through pharmacological inhibition and genetic depletion of P2Y12 as well as in vivo transfusion of wild-type (WT) or CD40L^−/− platelets, we demonstrate that the anti-tumor function of platelets is mediated through P2Y12-dependent CD40L release, which leads to CD8⁺ T cell activation by the CD40 receptor. Unlike P2Y12 inhibition, blocking platelets with aspirin does not prevent platelet CD40L release nor accelerate HCC in NAFLD mice. Similar findings were observed in liver metastasis models. All together, our study reveals a complex role of platelets in tumor regulation. Anti-platelet treatment without inhibiting CD40L release could be considered for liver cancer patients with NAFLD.

Original language	English (US)
Pages (from-to)	986-998.e5
Journal	Cancer cell
Volume	40
Issue number	9
DOIs	https://doi.org/10.1016/j.ccell.2022.08.004
State	Published - Sep 12 2022

Keywords

CD40L
HCC
NAFLD
P2Y12
liver metastasis
platelets

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2022.08.004

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Ma, C., Fu, Q., Diggs, L. P., McVey, J. C., McCallen, J., Wabitsch, S., Ruf, B., Brown, Z., Heinrich, B., Zhang, Q., Rosato, U., Wang, S., Cui, L., Berzofsky, J. A., Kleiner, D. E., Bosco, D. B., Wu, L. J., Lai, C. W., Rotman, Y., ... Greten, T. F. (2022). Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD. Cancer cell, 40(9), 986-998.e5. https://doi.org/10.1016/j.ccell.2022.08.004

Ma, C, Fu, Q, Diggs, LP, McVey, JC, McCallen, J, Wabitsch, S, Ruf, B, Brown, Z, Heinrich, B, Zhang, Q, Rosato, U, Wang, S, Cui, L, Berzofsky, JA, Kleiner, DE, Bosco, DB, Wu, LJ, Lai, CW, Rotman, Y, Xie, C, Korangy, F & Greten, TF 2022, 'Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD', Cancer cell, vol. 40, no. 9, pp. 986-998.e5. https://doi.org/10.1016/j.ccell.2022.08.004

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abstract = "Platelets, the often-overlooked component of the immune system, have been shown to promote tumor growth. Non-alcoholic fatty liver disease (NAFLD) is a common disease in the Western world and rising risk for hepatocellular carcinoma (HCC). Unexpectedly, we observed that platelets can inhibit the growth of established HCC in NAFLD mice. Through pharmacological inhibition and genetic depletion of P2Y12 as well as in vivo transfusion of wild-type (WT) or CD40L−/− platelets, we demonstrate that the anti-tumor function of platelets is mediated through P2Y12-dependent CD40L release, which leads to CD8+ T cell activation by the CD40 receptor. Unlike P2Y12 inhibition, blocking platelets with aspirin does not prevent platelet CD40L release nor accelerate HCC in NAFLD mice. Similar findings were observed in liver metastasis models. All together, our study reveals a complex role of platelets in tumor regulation. Anti-platelet treatment without inhibiting CD40L release could be considered for liver cancer patients with NAFLD.",

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AU - Ma, Chi

AU - Fu, Qiong

AU - Diggs, Laurence P.

AU - McVey, John C.

AU - McCallen, Justin

AU - Wabitsch, Simon

AU - Ruf, Benjamin

AU - Brown, Zachary

AU - Heinrich, Bernd

AU - Zhang, Qianfei

AU - Rosato, Umberto

AU - Wang, Sophie

AU - Cui, Linda

AU - Berzofsky, Jay A.

AU - Kleiner, David E.

AU - Bosco, Dale B.

AU - Wu, Long Jun

AU - Lai, Chunwei Walter

AU - Rotman, Yaron

AU - Xie, Changqing

AU - Korangy, Firouzeh

AU - Greten, Tim F.

PY - 2022/9/12

Y1 - 2022/9/12

N2 - Platelets, the often-overlooked component of the immune system, have been shown to promote tumor growth. Non-alcoholic fatty liver disease (NAFLD) is a common disease in the Western world and rising risk for hepatocellular carcinoma (HCC). Unexpectedly, we observed that platelets can inhibit the growth of established HCC in NAFLD mice. Through pharmacological inhibition and genetic depletion of P2Y12 as well as in vivo transfusion of wild-type (WT) or CD40L−/− platelets, we demonstrate that the anti-tumor function of platelets is mediated through P2Y12-dependent CD40L release, which leads to CD8+ T cell activation by the CD40 receptor. Unlike P2Y12 inhibition, blocking platelets with aspirin does not prevent platelet CD40L release nor accelerate HCC in NAFLD mice. Similar findings were observed in liver metastasis models. All together, our study reveals a complex role of platelets in tumor regulation. Anti-platelet treatment without inhibiting CD40L release could be considered for liver cancer patients with NAFLD.

AB - Platelets, the often-overlooked component of the immune system, have been shown to promote tumor growth. Non-alcoholic fatty liver disease (NAFLD) is a common disease in the Western world and rising risk for hepatocellular carcinoma (HCC). Unexpectedly, we observed that platelets can inhibit the growth of established HCC in NAFLD mice. Through pharmacological inhibition and genetic depletion of P2Y12 as well as in vivo transfusion of wild-type (WT) or CD40L−/− platelets, we demonstrate that the anti-tumor function of platelets is mediated through P2Y12-dependent CD40L release, which leads to CD8+ T cell activation by the CD40 receptor. Unlike P2Y12 inhibition, blocking platelets with aspirin does not prevent platelet CD40L release nor accelerate HCC in NAFLD mice. Similar findings were observed in liver metastasis models. All together, our study reveals a complex role of platelets in tumor regulation. Anti-platelet treatment without inhibiting CD40L release could be considered for liver cancer patients with NAFLD.

KW - CD40L

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KW - NAFLD

KW - P2Y12

KW - liver metastasis

KW - platelets

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Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD

Abstract

Keywords

ASJC Scopus subject areas

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