Antitumor immunity targeting fibroblast activation protein‑α in a mouse Lewis lung carcinoma model

Xie,Junping; Yuan,Shiyang; Peng,Laishui; Li,Huanyu; Niu,Linxia; Xu,Hui; Guo,Xiaolin; Yang,Mei; Duan,Fengying

doi:10.3892/ol.2020.11637

Antitumor immunity targeting fibroblast activation protein‑α in a mouse Lewis lung carcinoma model

Authors:
- Junping Xie
- Shiyang Yuan
- Laishui Peng
- Huanyu Li
- Linxia Niu
- Hui Xu
- Xiaolin Guo
- Mei Yang
- Fengying Duan
View Affiliations

Affiliations: Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: May 18, 2020 https://doi.org/10.3892/ol.2020.11637
Pages: 868-876
Copyright: © Xie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The tumor stromal microenvironment is an integral part of the occurrence and development of tumor. Cancer‑associated fibroblasts (CAFs) are a key component of most tumor stromal microenvironments. The present study aimed to investigate the use of CAFs‑targeted immunotherapy to fibroblast activation protein‑α (FAP‑α) expressed in CAFs. Recombinant adenoviral vectors containing the mouse FAP‑α cDNA (rAd‑FAP‑α) were constructed. C57BL/6 mice were immunized with rAd‑FAP‑α infected dendritic cells (DCs) against FAP‑α, which is overexpress in CAFs. The results demonstrated that mice vaccinated with rAd‑FAP‑α DCs gave rise to potent FAP‑α‑specific cytotoxic T lymphocytes capable of lysing Lewis lung cancer (LLC) CAFs. Furthermore, mice vaccinated with rAd‑FAP‑α‑transduced DCs induced an effective therapeutic or protective antitumor immunity to LLC in a subcutaneous model, and prolonged overall survival time compared with mice vaccinated with the control recombinant adenovirus‑transduced DCs (rAd‑c DCs) or DCs alone. The results of the present study suggested that FAP‑α, which is preferentially expressed in CAFs, may be considered as a potential target for killing or destroying CAFs within the tumor stromal microenvironment, and may be exploited to develop immunogenic tumor vaccines.

View Figures

View References

1	Lai D, Ma L and Wang F: Fibroblast activation protein regulates tumor-associated fibroblasts and epithelial ovarian cancer cells. Int J Oncol. 41:541–550. 2012. View Article : Google Scholar : PubMed/NCBI
2	Giannoni E, Bianchini F, Calorini L and Chiarugi P: Cancer associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness. Antioxid Redox Signal. 14:2361–2371. 2011. View Article : Google Scholar : PubMed/NCBI
3	Puré E and Lo A: Can targeting stroma pave the way to enhanced antitumor immunity and immunotherapy of solid tumors? Cancer Immunol Res. 4:269–278. 2016. View Article : Google Scholar : PubMed/NCBI
4	Liu T, Zhou L, Li D, Andl T and Zhang Y: Cancer-associated fibroblasts build and secure the tumor microenvironment. Front Cell Dev Biol. 7:602019. View Article : Google Scholar : PubMed/NCBI
5	Erez N, Truitt M, Olson P, Arron ST and Hanahan D: Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell. 17:135–147. 2010. View Article : Google Scholar : PubMed/NCBI
6	Ohshio Y, Teramoto K, Hanaoka J, Tezuka N, Itoh Y, Asai T, Daigo Y and Ogasawara K: Cancer-associated fibroblast-targeted strategy enhances antitumor immune responses in dendritic cell-based vaccine. Cancer Sci. 106:134–142. 2015. View Article : Google Scholar : PubMed/NCBI
7	Barron DA and Rowley DR: The reactive stroma microenvironment and prostate cancer progression. Endocr Relat Cancer. 19:R187–R204. 2012. View Article : Google Scholar : PubMed/NCBI
8	Gascard P and Tlsty TD: Carcinoma-associated fibroblasts: Orchestrating the composition of malignancy. Genes Dev. 30:1002–1019. 2016. View Article : Google Scholar : PubMed/NCBI
9	Valkenburg KC, de Groot AE and Pienta KJ: Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol. 15:366–381. 2018. View Article : Google Scholar : PubMed/NCBI
10	Elenbaas B and Weinberg RA: Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res. 264:169–184. 2001. View Article : Google Scholar : PubMed/NCBI
11	Xing F, Saidou J and Watabe K: Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci (Landmark Ed). 15:166–179. 2010. View Article : Google Scholar : PubMed/NCBI
12	Bhowmick NA, Neilson EG and Moses HL: Stromal fibroblasts in cancer initiation and progression. Nature. 432:332–337. 2004. View Article : Google Scholar : PubMed/NCBI
13	Santos AM, Jung J, Aziz N, Kissil JL and Puré E: Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest. 119:3613–3625. 2009. View Article : Google Scholar : PubMed/NCBI
14	Edosada CY, Quan C, Tran T, Pham V, Wiesmann C, Fairbrother W and Wolf BB: Peptide substrate profiling defines fibroblast activation protein as an endopeptidase of strict Gly(2)-Pro(1)-cleaving specificity. FEBS Lett. 580:1581–1586. 2006. View Article : Google Scholar : PubMed/NCBI
15	Edosada CY, Quan C, Wiesmann C, Tran T, Sutherlin D, Reynolds M, Elliott JM, Raab H, Fairbrother W and Wolf BB: Selective inhibition of fibroblast activation protein protease based on dipeptide substrate specificity. J Biol Chem. 281:7437–7444. 2006. View Article : Google Scholar : PubMed/NCBI
16	Jansen K, Heirbaut L, Cheng JD, Joossens J, Ryabtsova O, Cos P, Maes L, Lambeir AM, De Meester I, Augustyns K, et al: Selective inhibitors of fibroblast activation protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine scaffold. ACS Med Chem Lett. 4:491–496. 2013. View Article : Google Scholar : PubMed/NCBI
17	Meadows SA, Edosada CY, Mayeda M, Tran T, Quan C, Raab H, Wiesmann C and Wolf BB: Ala657 and conserved active site residues promote fibroblast activation protein endopeptidase activity via distinct mechanisms of transition state stabilization. Biochemistry. 46:4598–4605. 2007. View Article : Google Scholar : PubMed/NCBI
18	Ostermann E, Garin-Chesa P, Heider KH, Kalat M, Lamche H, Puri C, Kerjaschki D, Rettig WJ and Adolf GR: Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin Cancer Res. 14:4584–4592. 2008. View Article : Google Scholar : PubMed/NCBI
19	Jia J, Martin TA, Ye L and Jiang WG: FAP-α (Fibroblast activation protein-α) is involved in the control of human breast cancer cell line growth and motility via the FAK pathway. BMC Cell Biol. 15:162014. View Article : Google Scholar : PubMed/NCBI
20	Nyberg-Hoffman C, Shabram P, Li W, Giroux D and Aguilar-Cordova E: Sensitivity and reproducibility in adenoviral infectious titer determination. Nat Med. 3:808–811. 1997. View Article : Google Scholar : PubMed/NCBI
21	Xie J, Xiong L, Tao X, Li X, Su Y, Hou X and Shi H: Antitumor effects of murine bone marrow-derived dendritic cells infected with xenogeneic livin alpha recombinant adenoviral vectors against lewis lung carcinoma. Lung Cancer. 68:338–345. 2010. View Article : Google Scholar : PubMed/NCBI
22	Lee J, Fassnacht M, Nair S, Boczkowski D and Gilboa E: Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts. Cancer Res. 65:11156–11163. 2005. View Article : Google Scholar : PubMed/NCBI
23	Puré E and Blomberg R: Pro-tumorigenic roles of fibroblast activation protein in cancer: Back to the basics. Oncogene. 37:4343–4357. 2018. View Article : Google Scholar : PubMed/NCBI
24	van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A and Boon T: A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 254:1643–1647. 1991. View Article : Google Scholar : PubMed/NCBI
25	Willimsky G, Czéh M, Loddenkemper C, Gellermann J, Schmidt K, Wust P, Stein H and Blankenstein T: Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness. J Exp Med. 205:1687–1700. 2008. View Article : Google Scholar : PubMed/NCBI
26	Dunn GP, Koebel CM and Schreiber RD: Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 6:836–848. 2006. View Article : Google Scholar : PubMed/NCBI
27	Speiser DE, Baumgaertner P, Barbey C, Rubio-Godoy V, Moulin A, Corthesy P, Devevre E, Dietrich PY, Rimoldi D, Liénard D, et al: A novel approach to characterize clonality and differentiation of human melanoma-specific T cell responses: Spontaneous priming and efficient boosting by vaccination. J Immunol. 177:1338–1348. 2006. View Article : Google Scholar : PubMed/NCBI
28	Rosenberg SA, Sherry RM, Morton KE, Scharfman WJ, Yang JC, Topalian SL, Royal RE, Kammula U, Restifo NP, Hughes MS, et al: Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8 + T cells in patients with melanoma. J Immunol. 175:6169–6176. 2005. View Article : Google Scholar : PubMed/NCBI
29	Valmori D, Souleimanian NE, Tosello V, Bhardwaj N, Adams S, O'Neill D, Pavlick A, Escalon JB, Cruz CM, Angiulli A, et al: Vaccination with NY-ESO-1 protein and CpG in montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming. Proc Natl Acad Sci USA. 104:8947–8952. 2007. View Article : Google Scholar : PubMed/NCBI
30	Garin-Chesa P, Old LJ and Rettig WJ: Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA. 87:7235–7239. 1990. View Article : Google Scholar : PubMed/NCBI
31	Dolznig H, Schweifer N, Puri C, Kraut N, Rettig WJ, Kerjaschki D and Garin-Chesa P: Characterization of cancer stroma markers: In silico analysis of an mRNA expression database for fibroblast activation protein and endosialin. Cancer Immun. 5:102005.PubMed/NCBI
32	Scarfò I and Maus MV: Current approaches to increase CAR T cell potency in solid tumors: Targeting the tumor microenvironment. J Immunother Cancer. 5:282017. View Article : Google Scholar : PubMed/NCBI
33	Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL and Weinberg RA: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 121:335–348. 2005. View Article : Google Scholar : PubMed/NCBI
34	Chen WT and Kelly T: Seprase complexes in cellular invasiveness. Cancer Metastasis Rev. 22:259–269. 2003. View Article : Google Scholar : PubMed/NCBI
35	Rosenblum JS and Kozarich JW: Prolyl peptidases: A serine protease subfamily with high potential for drug discovery. Curr Opin Chem Biol. 7:496–504. 2003. View Article : Google Scholar : PubMed/NCBI
36	Hofheinz RD, al-Batran SE, Hartmann F, Hartung G, Jäger D, Renner C, Tanswell P, Kunz U, Amelsberg A, Kuthan H and Stehle G: Stromal antigen targeting by a humanised monoclonal antibody: An early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Onkologie. 26:44–48. 2003.PubMed/NCBI
37	Scott AM, Wiseman G, Welt S, Adjei A, Lee FT, Hopkins W, Divgi CR, Hanson LH, Mitchell P, Gansen DN, et al: A phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res. 9:1639–1647. 2003.PubMed/NCBI
38	Kawase T, Yasui Y, Nishina S, Hara Y, Yanatori I, Tomiyama Y, Nakashima Y, Yoshida K, Kishi F, Nakamura M and Hino K: Fibroblast activation protein-α-expressing fibroblasts promote the progression of pancreatic ductal adenocarcinoma. BMC Gastroenterol. 15:1092015. View Article : Google Scholar : PubMed/NCBI
39	Brennen WN, Rosen DM, Wang H, Isaacs JT and Denmeade SR: Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. J Natl Cancer Inst. 104:1320–1334. 2012. View Article : Google Scholar : PubMed/NCBI
40	Schreiber H and Rowley DA: Cancer. Awakening immunity. Science. 330:761–762. 2010. View Article : Google Scholar : PubMed/NCBI
41	Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA and Fearon DT: Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 330:827–830. 2010. View Article : Google Scholar : PubMed/NCBI