Abstract
Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic. We recently reported that tumor stroma-derived angiopoietin-like protein 2 (ANGPTL2) has tumor suppressive activity by enhancing dendritic cell-mediated CD8+ T cell anti-tumor immune responses. However, a direct impact of ANGPTL2 on ICI anti-tumor effect remains unclear. Here, we use a murine syngeneic model to show that host ANGPTL2 facilitates CD8+ T cell cross-priming and contributes to anti-tumor responses to ICIs in this context. Importantly, our analysis of public datasets indicated that ANGPTL2 expression is associated with positive responses to ICI therapy by human melanoma patients. We conclude that ANGPTL2-mediated stromal cell crosstalk facilitates anti-tumor immunity and ICI responsiveness. These findings overall provide novel insight into ANGPTL2 anti-tumor function and regulation of ICI-induced anti-tumor immunity.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
All data are available from the corresponding author on reasonable request.
References
Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24:541–50.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.
Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.
Meng X, Huang Z, Teng F, Xing L, Yu J. Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy. Cancer Treat. Rev. 2015;41:868–76.
Zhang J, Huang D, Saw PE, Song E. Turning cold tumors hot: from molecular mechanisms to clinical applications. Trends Immunol. 2022;43:523–45.
Oike Y, Yasunaga K, Ito Y, Matsumoto Sichiro, Maekawa H, Morisada T, et al. Angiopoietin-related growth factor (AGF) promotes epidermal proliferation, remodeling, and regeneration. Proc Natl Acad Sci USA. 2003;100:9494–9.
Hato T, Tabata M, Oike Y. The role of angiopoietin-like proteins in angiogenesis and metabolism. Trends Cardiovasc. Med. 2008;18:6–14.
Kadomatsu T, Endo M, Miyata K, Oike Y. Diverse roles of ANGPTL2 in physiology and pathophysiology. Trends Endocrinol Metab. 2014;25:245–54.
Horiguchi H, Kadomatsu T, Kurahashi R, Hara C, Miyata K, Baba M, et al. Dual functions of angiopoietin-like protein 2 signaling in tumor progression and anti-tumor immunity. Genes Dev. 2019;33:1641–56.
Sharma P, Allison JP. The future of immune checkpoint therapy. Science (80-). 2015;348:56–61.
Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer. 2016;16:275–87.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio Cancer Genomics Portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.
Liu D, Schilling B, Liu D, Sucker A, Livingstone E, Jerby-Amon L, et al. Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma. Nat Med. 2019;25. https://doi.org/10.1038/s41591-019-0654-5.
Wang MM, Coupland SE, Aittokallio T, Figueiredo CR. Resistance to immune checkpoint therapies by tumour-induced T-cell desertification and exclusion: key mechanisms, prognostication and new therapeutic opportunities. Br J Cancer. 2023. https://doi.org/10.1038/s41416-023-02361-4.
Barry KC, Hsu J, Broz ML, Cueto FJ, Binnewies M, Combes AJ, et al. A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments. Nat Med. 2018;24:1178–91.
Bulgarelli J, Tazzari M, Granato AM, Ridolfi L, Maiocchi S, de Rosa F, et al. Dendritic cell vaccination in metastatic melanoma turns “non-T cell inflamed” into “T-cell inflamed” tumors. Front Immunol. 2019;10. https://doi.org/10.3389/fimmu.2019.02353.
Lövgren T, Wolodarski M, Wickström S, Edbäck U, Wallin M, Martell E, et al. Complete and long-lasting clinical responses in immune checkpoint inhibitor-resistant, metastasized melanoma treated with adoptive T cell transfer combined with DC vaccination. Oncoimmunology. 2020;9. https://doi.org/10.1080/2162402X.2020.1792058.
Yu J, Sun H, Cao W, Song Y, Jiang Z. Research progress on dendritic cell vaccines in cancer immunotherapy. Exp Hematol Oncol. 2022;11. https://doi.org/10.1186/s40164-022-00257-2.
Yarchoan M, Albacker LA, Hopkins AC, Montesion M, Murugesan K, Vithayathil TT, et al. PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight. 2019;4. https://doi.org/10.1172/jci.insight.126908.
Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127. https://doi.org/10.1172/JCI91190.
Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science. 2018;362. https://doi.org/10.1126/science.aar3593.
Litchfield K, Reading JL, Puttick C, Thakkar K, Abbosh C, Bentham R, et al. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 2021;184. https://doi.org/10.1016/j.cell.2021.01.002.
Horiguchi H, Kadomatsu T, Miyata K, Terada K, Sato M, Torigoe D, et al. Stroma-derived ANGPTL2 establishes an anti-tumor microenvironment during intestinal tumorigenesis. Oncogene. 2021;40:55–67.
Kikuchi R, Tsuda H, Kozaki KI, Kanai Y, Kasamatsu T, Sengoku K, et al. Frequent inactivation of a putative tumor suppressor, angiopoietin-like protein 2, in ovarian cancer. Cancer Res. 2008;68:5067–75.
Aoi J, Endo M, Kadomatsu T, Miyata K, Nakano M, Horiguchi H, et al. Angiopoietin-like protein 2 is an important facilitator of inflammatory carcinogenesis and metastasis. Cancer Res. 2011;71:7502–12.
Endo M, Nakano M, Kadomatsu T, Fukuhara S, Kuroda H, Mikami S, et al. Tumor cell-derived angiopoietin-like protein ANGPTL2 is a critical driver of metastasis. Cancer Res. 2012;72:1784–94.
Horiguchi H, Endo M, Miyamoto Y, Sakamoto Y, Odagiri H, Masuda T, et al. Angiopoietin-like protein 2 renders colorectal cancer cells resistant to chemotherapy by activating spleen tyrosine kinase-phosphoinositide 3-kinase-dependent anti-apoptotic signaling. Cancer Sci. 2014;105:1550–9.
Osumi H, Horiguchi H, Kadomatsu T, Tashiro K, Morinaga J, Takahashi T, et al. Tumor cell-derived angiopoietin-like protein 2 establishes a preference for glycolytic metabolism in lung cancer cells. Cancer Sci. 2020;111:1241–53.
Horiguchi H, Kadomatsu T, Yumoto S, Masuda T, Miyata K, Yamamura S, et al. Tumor cell-derived ANGPTL2 promotes β-catenin-driven intestinal tumorigenesis. Oncogene. 2022;41:4028–41.
Kadomatsu T, Hara C, Kurahashi R, Horiguchi H, Morinaga J, Miyata K, et al. ANGPTL2-mediated epigenetic repression of MHC-I in tumor cells accelerates tumor immune evasion. Mol Oncol. 2023. https://doi.org/10.1002/1878-0261.13490.
Netsirisawan P, Chokchaichamnankit D, Srisomsap C, Svasti J, Champattanachai V. Proteomic analysis reveals aberrant o-glcnacylation of extracellular proteins from breast cancer cell secretion. Cancer Genomics Proteomics. 2015;12:201–9.
Ho WL, Hsu WM, Huang MC, Kadomatsu K, Nakagawara A. Protein glycosylation in cancers and its potential therapeutic applications in neuroblastoma. J. Hematol. Oncol. 2016;9:1–15.
Peixoto A, Relvas-Santos M, Azevedo R, Lara Santos L, Ferreira JA. Protein glycosylation and tumor microenvironment alterations driving cancer hallmarks. Front Oncol. 2019;9. https://doi.org/10.3389/fonc.2019.00380.
Thomas D, Rathinavel AK, Radhakrishnan P. Altered glycosylation in cancer: a promising target for biomarkers and therapeutics. Biochim Biophys Acta—Rev Cancer. 2021;1875. https://doi.org/10.1016/j.bbcan.2020.188464.
Kim I, Moon SO, Koh KN, Kim H, Uhm CS, Kwak HJ, et al. Molecular cloning, expression, and characterization of angiopoietin- related protein. Angiopoietin-related protein induces endothelial cell sprouting. J Biol Chem. 1999;274:26523–8.
Tabata M, Kadomatsu T, Fukuhara S, Miyata K, Ito Y, Endo M, et al. Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation and obesity-related systemic insulin resistance. Cell Metab. 2009;10:178–88.
Horiguchi H, Endo M, Kawane K, Kadomatsu T, Terada K, Morinaga J, et al. ANGPTL2 expression in the intestinal stem cell niche controls epithelial regeneration and homeostasis. EMBO J. 2017;36:409–24.
Motokawa I, Endo M, Terada K, Horiguchi H, Miyata K, Kadomatsu T, et al. Interstitial pneumonia induced by bleomycin treatment is exacerbated in Angptl2-deficient mice. Am J Physiol—Lung Cell Mol Physiol. 2016;311:L704–L713.
Acknowledgements
The authors thank Kiyoka Tabu, Noriko Shirai, and Sayomi Iwaki for technical assistance. This work was supported by the Scientific Research Fund of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (grant 23K06638 to HH, grant 21K07101 to TK), the Takeda Science Foundation (HH), a Tasaki Memorial Research Grant for 2022 (HH), a grant from the Center for Metabolic Regulation of Healthy Aging (CMHA) (HH), and the Kato Memorial Bioscience Foundation (TK).
Author information
Authors and Affiliations
Contributions
HH designed the study, performed and analyzed experiments, and wrote the paper. TK designed and supervised the study. TY, SY, TH, and MS performed and analyzed experiments. KT provided recombinant ANGPTL2 protein. KM provided Angptl2 mutant mice. YI, TK, and SF collected human samples. TM supervised the study. YO coordinated, designed, and supervised the study and wrote the paper. All authors discussed the data and commented on the paper.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Horiguchi, H., Kadomatsu, T., Yamashita, T. et al. Tumor stroma-derived ANGPTL2 potentiates immune checkpoint inhibitor efficacy. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00757-9
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41417-024-00757-9