Endothelial Cell Notch Signaling Programs Cancer-associated Fibroblasts to Promote Tumor Immune Evasion

Overview

Journal Res Sq

Date 2024 Jul 1

PMID 38947054

Authors

Yu Zhu

Menglan Xiang

Kevin F Brulois

Nicole H Lazarus

Junliang Pan

Eugene C Butcher

Affiliations

Soon will be listed here.

Abstract

Stromal cells within the tumor tissue promote immune evasion as a critical strategy for cancer development and progression, but the underlying mechanisms remain poorly understood. In this study, we explore the role of endothelial cells (ECs) in the regulation of the immunosuppressive tumor microenvironment. Using mouse pancreatic ductal adenocarcinoma (PDAC) models, we found that canonical Notch signaling in endothelial cells suppresses the recruitment of antitumor T cells and promotes tumor progression by inhibiting the pro-inflammatory functions of cancer-associated fibroblasts (CAFs). Abrogation of endothelial Notch signaling modulates EC-derived angiocrine factors to enhance the pro-inflammatory activities of CAFs, which drive CXCL9/10-CXCR3-mediated T cell recruitment to inhibit tumor growth. Additionally, abrogation of endothelial Notch unleashed interferon gamma responses in the tumor microenvironment, upregulated PDL1 expression on tumor cells, and sensitized PDAC to PD1-based immunotherapy. Collectively, these data uncover a pivotal role of endothelial cells in shaping the immunosuppressive microenvironment, and suggest the potential of targeting EC-CAF interaction as a novel therapeutic modality to boost antitumor immunity.

References

Feig C, Jones J, Kraman M, Wells R, Deonarine A, Chan D . Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013; 110(50):20212-7. PMC: 3864274. DOI: 10.1073/pnas.1320318110. View

Rhim A, Oberstein P, Thomas D, Mirek E, Palermo C, Sastra S . Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014; 25(6):735-47. PMC: 4096698. DOI: 10.1016/j.ccr.2014.04.021. View

Fleig S, Kapanadze T, Bernier-Latmani J, Lill J, Wyss T, Gamrekelashvili J . Loss of vascular endothelial notch signaling promotes spontaneous formation of tertiary lymphoid structures. Nat Commun. 2022; 13(1):2022. PMC: 9018798. DOI: 10.1038/s41467-022-29701-x. View

Takebe N, Miele L, Harris P, Jeong W, Bando H, Kahn M . Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol. 2015; 12(8):445-64. PMC: 4520755. DOI: 10.1038/nrclinonc.2015.61. View

Ntziachristos P, Lim J, Sage J, Aifantis I . From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell. 2014; 25(3):318-34. PMC: 4040351. DOI: 10.1016/j.ccr.2014.02.018. View

Zeng Q, Li S, Chepeha D, Giordano T, Li J, Zhang H . Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell. 2005; 8(1):13-23. DOI: 10.1016/j.ccr.2005.06.004. View

Rehman A, Wang C . Notch signaling in the regulation of tumor angiogenesis. Trends Cell Biol. 2006; 16(6):293-300. DOI: 10.1016/j.tcb.2006.04.003. View

van der Woude L, Gorris M, Halilovic A, Figdor C, de Vries I . Migrating into the Tumor: a Roadmap for T Cells. Trends Cancer. 2017; 3(11):797-808. DOI: 10.1016/j.trecan.2017.09.006. View

Thommen D, Schumacher T . T Cell Dysfunction in Cancer. Cancer Cell. 2018; 33(4):547-562. PMC: 7116508. DOI: 10.1016/j.ccell.2018.03.012. View

10.

Ozdemir B, Pentcheva-Hoang T, Carstens J, Zheng X, Wu C, Simpson T . Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014; 25(6):719-34. PMC: 4180632. DOI: 10.1016/j.ccr.2014.04.005. View

11.

Mucciolo G, Araos Henriquez J, Jihad M, Pinto Teles S, Manansala J, Li W . EGFR-activated myofibroblasts promote metastasis of pancreatic cancer. Cancer Cell. 2023; 42(1):101-118.e11. DOI: 10.1016/j.ccell.2023.12.002. View

12.

Biffi G, Oni T, Spielman B, Hao Y, Elyada E, Park Y . IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer Discov. 2018; 9(2):282-301. PMC: 6368881. DOI: 10.1158/2159-8290.CD-18-0710. View

13.

Zhu Y, Knolhoff B, Meyer M, Nywening T, West B, Luo J . CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014; 74(18):5057-69. PMC: 4182950. DOI: 10.1158/0008-5472.CAN-13-3723. View

14.

Karin N . Chemokines and cancer: new immune checkpoints for cancer therapy. Curr Opin Immunol. 2018; 51:140-145. DOI: 10.1016/j.coi.2018.03.004. View

15.

Zhang L, Conejo-Garcia J, Katsaros D, Gimotty P, Massobrio M, Regnani G . Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003; 348(3):203-13. DOI: 10.1056/NEJMoa020177. View

16.

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C . Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313(5795):1960-4. DOI: 10.1126/science.1129139. View

17.

Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida A, Ponz-Sarvise M . Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017; 214(3):579-596. PMC: 5339682. DOI: 10.1084/jem.20162024. View

18.

Adams R . Molecular control of arterial-venous blood vessel identity. J Anat. 2003; 202(1):105-12. PMC: 1571062. DOI: 10.1046/j.1469-7580.2003.00137.x. View

19.

Hingorani S, Wang L, Multani A, Combs C, Deramaudt T, Hruban R . Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005; 7(5):469-83. DOI: 10.1016/j.ccr.2005.04.023. View

20.

Tan W, Zhang W, Strasner A, Grivennikov S, Cheng J, Hoffman R . Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature. 2011; 470(7335):548-53. PMC: 3166217. DOI: 10.1038/nature09707. View