Solid tumors are characterized by abundant extracellular matrix originating from cancer-associated fibroblasts (CAFs). High collagen content can trigger the collapse of vascular system in the tumor and form physical barrier that eventually impedes the penetration of drug particles and cytotoxic immune cells. Moreover, CAFs is able to promote the enrichment of tumor-associated macrophages (TAMs) and differentiation of myeloid-derived suppressor cells (MDSCs) that work in concert to develop a highly immunosuppressive tumor microenvironment (TME). In this study, we investigated if halofuginone, an antifibrotic drug, can augment the therapeutic effects of oncolytic vesicular stomatitis virus (VSV). The results revealed that halofuginone significantly disrupts the collagen network in tumors and promotes the distribution of VSV and infiltration of CD8+ T cells (p < 0.0001). Combined treatment of VSV and halofuginone also modulates the immunosuppressive TME via deletion of TAM, MDSCs, and regulatory T cells (Tregs). Collectively, the combination therapy remarkably inhibits the tumor growth in multiple murine models and prolongs survival of mice. The results demonstrate the clinical potential of halofuginone in combination with oncolytic virus.
StojdlDF, LichtyB, KnowlesS, et al.Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med, 2000; 6:821–825.
3.
ChioccaEA, RabkinSD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res, 2014; 2:295–300.
4.
KaufmanHL, KohlhappFJ, ZlozaA. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov, 2015; 14:642–662.
5.
FukuharaH, InoY, TodoT. Oncolytic virus therapy: a new era of cancer treatment at dawn. Cancer Sci, 2016; 107:1373–1379.
6.
RajaJ, LudwigJM, GettingerSN, et al.Oncolytic virus immunotherapy: future prospects for oncology. J Immunother Cancer, 2018; 6:140.
7.
MelzerMK, Lopez-MartinezA, AltomonteJ. Oncolytic vesicular stomatitis virus as a viro-immunotherapy: defeating cancer with a “Hammer” and “Anvil.”. Biomedicines, 2017; 5:8.
8.
FeltSA, GrdzelishviliVZ. Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update. J Gen Virol, 2017; 98:2895–2911.
9.
HastieE, GrdzelishviliVZ. Vesicular stomatitis virus as a flexible platform for oncolytic virotherapy against cancer. J Gen Virol, 2012; 93:2529–2545.
10.
ShinozakiK, EbertO, SuriawinataA, et al.Prophylactic alpha interferon treatment increases the therapeutic index of oncolytic vesicular stomatitis virus virotherapy for advanced hepatocellular carcinoma in immune-competent rats. J Virol, 2005; 79:13705–13713.
11.
YamakiM, ShinozakiK, SakaguchiT, et al.The potential of recombinant vesicular stomatitis virus-mediated virotherapy against metastatic colon cancer. Int J Mol Med, 2013; 31:299–306.
12.
DiazRM, GalivoF, KottkeT, et al.Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus. Cancer Res, 2007; 67:2840–2848.
13.
AltomonteJ, WuL, ChenL, et al.Exponential enhancement of oncolytic vesicular stomatitis virus potency by vector-mediated suppression of inflammatory responses in vivo. Mol Ther, 2008; 16:146–153.
14.
WuL, HuangTG, MeseckM, et al.rVSV(M Delta 51)-M3 is an effective and safe oncolytic virus for cancer therapy. Hum Gene Ther, 2008; 19:635–647.
15.
ZhangL, SteeleMB, JenksN, et al.Safety studies in tumor and non-tumor-bearing mice in support of clinical trials using oncolytic VSV-IFNβ-NIS. Hum Gene Ther Clin Dev, 2016; 27:111–122.
16.
PatelMR, JacobsonBA, JiY, et al.Vesicular stomatitis virus expressing interferon-β is oncolytic and promotes antitumor immune responses in a syngeneic murine model of non-small cell lung cancer. Oncotarget, 2015; 6:33165–33177.
17.
YoonAR, HongJ, LiY, et al.Mesenchymal stem cell-mediated delivery of an oncolytic adenovirus enhances antitumor efficacy in hepatocellular carcinoma. Cancer Res, 2019; 79:4503–4514.
18.
KimPH, SohnJH, ChoiJW, et al.Active targeting and safety profile of PEG-modified adenovirus conjugated with herceptin. Biomaterials, 2011; 32:2314–2326.
19.
MuhammadT, SakhawatA, KhanAA, et al.Mesenchymal stem cell-mediated delivery of therapeutic adenoviral vectors to prostate cancer. Stem Cell Res Ther, 2019; 10:190.
20.
Diop-FrimpongB, ChauhanVP, KraneS, et al.Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci U S A, 2011; 108:2909–2914.
21.
CostaA, KiefferY, Scholer-DahirelA, et al.Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell, 2018; 33:463–479.e410.
22.
LakinsMA, GhoraniE, MunirH, et al.Cancer-associated fibroblasts induce antigen-specific deletion of CD8 (+) T Cells to protect tumour cells. Nat Commun, 2018; 9:948.
23.
SuS, ChenJ, YaoH, et al.CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell, 2018; 172:841–856.e816.
24.
Elahi-GedwilloKY, CarlsonM, ZettervallJ, et al.Antifibrotic therapy disrupts stromal barriers and modulates the immune landscape in pancreatic ductal adenocarcinoma. Cancer Res, 2019; 79:372–386.
25.
LeibaM, JakubikovaJ, KlippelS, et al.Halofuginone inhibits multiple myeloma growth in vitro and in vivo and enhances cytotoxicity of conventional and novel agents. Br J Haematol, 2012; 157:718–731.
26.
JuárezP, MohammadKS, YinJJ, et al.Halofuginone inhibits the establishment and progression of melanoma bone metastases. Cancer Res, 2012; 72:6247–6256.
27.
LamoraA, MullardM, AmiaudJ, et al.Anticancer activity of halofuginone in a preclinical model of osteosarcoma: inhibition of tumor growth and lung metastases. Oncotarget, 2015; 6:14413–14427.
28.
HuoS, YuH, LiC, et al.Effect of halofuginone on the inhibition of proliferation and invasion of hepatocellular carcinoma HepG2 cell line. Int J Clin Exp Pathol, 2015; 8:15863–15870.
29.
Demiroglu-ZergerogluA, TurhalG, TopalH, et al.Anticarcinogenic effects of halofuginone on lung-derived cancer cells. Cell Biol Int, 2020; 44:1934–1944.
30.
Bourgeois-DaigneaultMC, RoyDG, FallsT, et al.Oncolytic vesicular stomatitis virus expressing interferon-γ has enhanced therapeutic activity. Mol Ther Oncolytics, 2016; 3:16001.
31.
Moerdyk-SchauweckerM, HwangSI, GrdzelishviliVZ. Analysis of virion associated host proteins in vesicular stomatitis virus using a proteomics approach. Virol J, 2009; 6:166.
32.
KuzetSE, GaggioliC. Fibroblast activation in cancer: when seed fertilizes soil. Cell Tissue Res, 2016; 365:607–619.
33.
De MarcoP, LappanoR, De FrancescoEM, et al.GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1β/IL1R1 response. Sci Rep, 2016; 6:24354.
34.
KramerN, SchmöllerlJ, UngerC, et al.Autocrine WNT2 signaling in fibroblasts promotes colorectal cancer progression. Oncogene, 2017; 36:5460–5472.
35.
IsellaC, TerrasiA, BellomoSE, et al.Stromal contribution to the colorectal cancer transcriptome. Nat Genet, 2015; 47:312–319.
36.
MezawaY, OrimoA. The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas. Cell Tissue Res, 2016; 365:675–689.
37.
GascardP, TlstyTD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev, 2016; 30:1002–1019.
38.
HuangAC, PostowMA, OrlowskiRJ, et al.T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature, 2017; 545:60–65.
39.
Le BoeufF, GebremeskelS, McMullenN, et al.Reovirus FAST protein enhances vesicular stomatitis virus oncolytic virotherapy in primary and metastatic tumor models. Mol Ther Oncolytics, 2017; 6:80–89.
40.
LiQ, WeiYQ, WenYJ, et al.Induction of apoptosis and tumor regression by vesicular stomatitis virus in the presence of gemcitabine in lung cancer. Int J Cancer, 2004; 112:143–149.
41.
IlettE, KottkeT, ThompsonJ, et al.Prime-boost using separate oncolytic viruses in combination with checkpoint blockade improves anti-tumour therapy. Gene Ther, 2017; 24:21–30.
42.
KoskeI, RösslerA, PippergerL, et al.Oncolytic virotherapy enhances the efficacy of a cancer vaccine by modulating the tumor microenvironment. Int J Cancer, 2019; 145:1958–1969.
43.
ZhaoY, CaoJ, MelamedA, et al.Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma. Proc Natl Acad Sci U S A, 2019; 116:2210–2219.
44.
IncioJ, LiuH, SubojP, et al.Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov, 2016; 6:852–869.
45.
GuedanS, RojasJJ, GrosA, et al.Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth. Mol Ther, 2010; 18:1275–1283.
46.
GaneshS, Gonzalez EdickM, IdamakantiN, et al.Relaxin-expressing, fiber chimeric oncolytic adenovirus prolongs survival of tumor-bearing mice. Cancer Res, 2007; 67:4399–4407.
47.
MpekrisF, PapageorgisP, PolydorouC, et al.Sonic-hedgehog pathway inhibition normalizes desmoplastic tumor microenvironment to improve chemo- and nanotherapy. J Control Release, 2017; 261:105–112.
48.
McKeeTD, GrandiP, MokW, et al.Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. Cancer Res, 2006; 66:2509–2513.
49.
MokW, BoucherY, JainRK. Matrix metalloproteinases-1 and -8 improve the distribution and efficacy of an oncolytic virus. Cancer Res, 2007; 67:10664–10668.
50.
CatenacciDV, JunttilaMR, KarrisonT, et al.Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J Clin Oncol, 2015; 33:4284–4292.
51.
PrestwichRJ, ErringtonF, IlettEJ, et al.Tumor infection by oncolytic reovirus primes adaptive antitumor immunity. Clin Cancer Res, 2008; 14:7358–7366.
52.
PrestwichRJ, HarringtonKJ, PandhaHS, et al.Oncolytic viruses: a novel form of immunotherapy. Expert Rev Anticancer Ther, 2008; 8:1581–1588.
53.
SobolPT, BoudreauJE, StephensonK, et al.Adaptive antiviral immunity is a determinant of the therapeutic success of oncolytic virotherapy. Mol Ther, 2011; 19:335–344.
54.
GuoZS, LiuZ, BartlettDL. Oncolytic immunotherapy: dying the right way is a key to eliciting potent antitumor immunity. Front Oncol, 2014; 4:74.
55.
ChenIX, ChauhanVP, PosadaJ, et al.Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proc Natl Acad Sci U S A, 2019; 116:4558–4566.
56.
SwieckiM, ColonnaM. Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol Rev, 2010; 234:142–162.
LundJM, AlexopoulouL, SatoA, et al.Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci U S A, 2004; 101:5598–5603.
59.
WeberCE, KuoPC. The tumor microenvironment. Surg Oncol, 2012; 21:172–177.
60.
HanahanD, WeinbergRA. Hallmarks of cancer: the next generation. Cell, 2011; 144:646–674.
61.
RabinovichGA, GabrilovichD, SotomayorEM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol, 2007; 25:267–296.
62.
ZhangR, QiF, ZhaoF, et al.Cancer-associated fibroblasts enhance tumor-associated macrophages enrichment and suppress NK cells function in colorectal cancer. Cell Death Dis, 2019; 10:273.
63.
XiangH, RamilCP, HaiJ, et al.Cancer-associated fibroblasts promote immunosuppression by inducing ROS-generating monocytic MDSCs in lung squamous cell carcinoma. Cancer Immunol Res, 2020; 8:436–450.
64.
FlavellRA, SanjabiS, WrzesinskiSH, et al.The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol, 2010; 10:554–567.
65.
YaghoubiN, SoltaniA, GhazviniK, et al.PD-1/PD-L1 blockade as a novel treatment for colorectal cancer. Biomed Pharmacother, 2019; 110:312–318.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
