Caveolin-1 (CAV1) is one of the members of the caveolae, and the role of CAV1 in esophageal cancer (ESCA) is not completely clear. In this study, we found that expression of CAV1 was downregulated in ESCA in The Cancer Genome Atlas and the Genotype-Tissue Expression (GTEx) database and we also use immunohistochemistry of tissue microarray for verification. Then, we used bioinformatics methods to investigate the prognostic value of CAV1, influence on immune cell infiltration in tumor microenvironment (TME) and responding to immunotherapy in ESCA. Our result indicated that CAV1 designs an inflamed TME in ESCA based on the evidence that CAV1 positively correlated with immunomodulators, immune score, stomal score, cancer immunity cycles, tumor-infiltrating immune cells, T cell inflamed score, and immune checkpoints. Immunophenoscore, Tumor Immune Dysfunction and Exclusion algorithms, and the mutation analysis show that the downregulated CAV1 expression indicated higher tumor mutation burden and higher rate of response to immune checkpoint inhibitors (ICIs) in the low-expression group. In a word, our study demonstrated the impact of CAV1 to the TME in ESCA and it may be a new target for ESCA immunotherapy. In addition, the expression of CAV1 can predict the clinical response to ICIs, which may provide clinical treatment guidance.
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References
1.
AyersM, LuncefordJ, NebozhynM, et al.IFN-γ-related MRNA profile predicts clinical response to PD-1 blockade. J Clin Invest, 2017; 127(8):2930–2940; doi: 10.1172/JCI91190
2.
BakerN, TuanRS. The less-often-traveled surface of stem cells: Caveolin-1 and caveolae in stem cells, tissue repair and regeneration. Stem Cell Res Ther, 2013; 4(4):90; doi: 10.1186/scrt276
3.
BarlesiF, DixmierA, DebieuvreD, et al.Effectiveness and safety of nivolumab in the treatment of lung cancer patients in France: Preliminary results from the real-world EVIDENS study. Oncoimmunology, 2020; 9(1):1744898; doi: 10.1080/2162402X.2020.1744898
BastianiM, PartonRG. Caveolae at a glance. J Cell Sci, 2010; 123(Pt 22):3831–3836; doi: 10.1242/jcs.070102
6.
BauerV, AhmetlićF, HömbergN, et al.Immune checkpoint blockade impairs immunosuppressive mechanisms of regulatory T cells in B-cell lymphoma. Transl Oncol, 2021; 14(9):101170; doi: 10.1016/j.tranon.2021.101170
7.
BernsmeierC, van der MerweS, PérianinA. Innate immune cells in cirrhosis. J Hepatol, 2020; 73(1):186–201; doi: 10.1016/j.jhep.2020.03.027
8.
BrayF, FerlayJ, SoerjomataramI, et al.Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018; 68(6):394–424; doi: 10.3322/caac.21492
9.
CharoentongP, FinotelloF, AngelovaM, et al.Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep, 2017; 18(1):248–262; doi: 10.1016/j.celrep.2016.12.019
FengS, WangY, WangX, et al.Caveolin-1 gene silencing promotes the activation of PI3K/AKT dependent on eralpha36 and the transformation of MCF10ACE. Sci China Life Sci, 2010; 53(5):598–605; doi: 10.1007/s11427-010-0100-x
12.
FialaGJ, MinguetS. Caveolin-1: The unnoticed player in TCR and BCR signaling. Adv Immunol, 2018; 137:83–133; doi: 10.1016/bs.ai.2017.12.002
13.
GerstenbergerW, WrageM, KettunenE, et al.Stromal caveolin-1 and caveolin-2 expression in primary tumors and lymph node metastases. Anal Cell Pathol (Amst), 2018; 2018:8651790; doi: 10.1155/2018/8651790
14.
GoldmanMJ, CraftB, HastieM, et al.Visualizing and interpreting cancer genomics data via the xena platform. Nat Biotechnol, 2020; 38(6):675–678; doi: 10.1038/s41587-020-0546-8
15.
GoodmanAM, KatoS, BazhenovaL, et al.Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther, 2017; 16(11):2598–2608; doi: 10.1158/1535-7163.MCT-17-0386
16.
GTEx Consortium. Human Genomics. The genotype-tissue expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science, 2015; 348(6235):648–660; doi: 10.1126/science.1262110
17.
GuptaR, ToufailyC, AnnabiB.Caveolin and cavin family members: Dual roles in cancer. Biochimie, 2014;107 Pt B:188–202; doi: 10.1016/j.biochi.2014.09.010
18.
HarrisJ, WerlingD, HopeJC, et al.Caveolae and caveolin in immune cells: Distribution and functions. Trends Immunol, 2002; 23(3):158–164; doi: 10.1016/s1471-4906(01)02161-5
19.
HsuP-K, ChienL-I, HuangC-S, et al.Treatment patterns and outcomes in patients with esophageal cancer: An analysis of a multidisciplinary tumor board database. Ann Surg Oncol, 2022; 29(1):572–585; doi: 10.1245/s10434-021-10568-z
20.
HuangD, YangB, YaoY, et al.Autophagic inhibition of caveolin-1 by compound Phyllanthus urinaria L. activates ubiquitination and proteasome degradation of β-catenin to suppress metastasis of hepatitis B-associated hepatocellular carcinoma. Front Pharmacol, 2021; 12:659325; doi: 10.3389/fphar.2021.659325
21.
HuangF-L, YuS-J. Esophageal cancer: Risk factors, genetic association, and treatment. Asian J Surg, 2018; 41(3):210–215; doi: 10.1016/j.asjsur.2016.10.005
22.
HuiE, CheungJ, ZhuJ, et al.T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science, 2017; 355(6332):1428–1433; doi: 10.1126/science.aaf1292
23.
JiaY, WangN, WangJ, et al.Down-regulation of stromal caveolin-1 expression in esophageal squamous cell carcinoma: A potent predictor of lymph node metastases, early tumor recurrence, and poor prognosis. Ann Surg Oncol, 2014; 21(1):329–336; doi: 10.1245/s10434-013-3225-x
24.
KellyRJ, AjaniJA, KuzdzalJ, et al.Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med, 2021; 384(13):1191–1203; doi: 10.1056/NEJMoa2032125
25.
KojimaT, ShahMA, MuroK, et al.Randomized phase III KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncol, 2020; 38(35):4138–4148; doi: 10.1200/JCO.20.01888
26.
LiT, FuJ, ZengZ, et al.TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res, 2020; 48(W1):W509–W514; doi: 10.1093/nar/gkaa407
27.
LiuZ, YuJ, WuR, et al.Rho/ROCK pathway regulates migration and invasion of esophageal squamous cell carcinoma by regulating caveolin-1. Med Sci Monit, 2017; 23:6174–6185; doi: 10.12659/msm.905820
28.
MayakondaA, LinD-C, AssenovY, et al.Maftools: Efficient and comprehensive analysis of somatic variants in cancer. Genome Res, 2018; 28(11):1747–1756; doi: 10.1101/gr.239244.118
29.
MuthS, KlaricA, RadsakM, et al.CD27 expression on Treg cells limits immune responses against tumors. J Mol Med (Berl), 2022; 100(3):439–449; doi: 10.1007/s00109-021-02116-9
30.
NagorsenD, VoigtS, BergE, et al.Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: Relation to local regulatory T cells, systemic T-cell response against tumor-associated antigens and survival. J Transl Med, 2007; 5:62; doi: 10.1186/1479-5876-5-62
31.
NagyÁ, LánczkyA, MenyhártO, et al.Author correction: Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep, 2018; 8(1):11515; doi: 10.1038/s41598-018-29514-3
32.
NakagawaH, WangTC, ZukerbergL, et al.The targeting of the cyclin D1 oncogene by an epstein-barr virus promoter in transgenic mice causes dysplasia in the tongue, esophagus and forestomach. Oncogene, 1997; 14(10):1185–1190; doi: 10.1038/sj.onc.1200937
33.
NewmanAM, LiuCL, GreenMR, et al.Robust enumeration of cell subsets from tissue expression profiles. Nat Methods, 2015; 12(5):453–457; doi: 10.1038/nmeth.3337
34.
Núñez-WehingerS, OrtizRJ, DíazN, et al.Caveolin-1 in cell migration and metastasis. Curr Mol Med, 2014; 14(2):255–274; doi: 10.2174/1566524014666140128112827
35.
ÓlafsdóttirHS, KlevebroF, NdegwaN, et al.Short-course compared to long-course palliative radiotherapy for oesophageal cancer: A single centre observational cohort study. Radiat Oncol, 2021; 16(1):153; doi: 10.1186/s13014-021-01880-9
36.
OpitzOG, HaradaH, SulimanY, et al.A mouse model of human oral-esophageal cancer. J Clin Invest, 2002; 110(6):761–769; doi: 10.1172/JCI15324
37.
ParkJH, LeeMY, HanHJ. A potential role for caveolin-1 in estradiol-17beta-induced proliferation of mouse embryonic stem cells: Involvement of Src, PI3K/Akt, and MAPKs pathways. Int J Biochem Cell Biol, 2009; 41(3):659–665; doi: 10.1016/j.biocel.2008.07.010
38.
RobinsonDR, WuY-M, LonigroRJ, et al.Integrative clinical genomics of metastatic cancer. Nature, 2017; 548(7667):297–303; doi: 10.1038/nature23306
39.
RodriguezDA, TapiaJC, FernandezJG, et al.Caveolin-1-mediated suppression of cyclooxygenase-2 via a beta-catenin-Tcf/Lef-dependent transcriptional mechanism reduced prostaglandin E2 production and survivin expression. Mol Biol Cell, 2009; 20(8):2297–2310; doi: 10.1091/mbc.e08-09-0939
40.
SamsteinRM, LeeC-H, ShoushtariAN, et al.Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet, 2019; 51(2):202–206; doi: 10.1038/s41588-018-0312-8
41.
ShackS, WangX-T, KokkonenGC, et al.Caveolin-induced activation of the phosphatidylinositol 3-kinase/Akt pathway increases arsenite cytotoxicity. Mol Cell Biol, 2003; 23(7):2407–2414; doi: 10.1128/MCB.23.7.2407-2414.2003
42.
ShortMW, BurgersKG, FryVT. Esophageal cancer. Am Fam Physician, 2017; 95(1):22–28.
43.
SiegelRL, MillerKD, JemalA. Cancer statistics, 2020. CA Cancer J Clin, 2020; 70(1):7–30; doi: 10.3322/caac.21590
44.
SongJ, WuL. Friend or foe: Prognostic and immunotherapy roles of BTLA in colorectal Cancer. Front Mol Biosci, 2020; 7:148; doi: 10.3389/fmolb.2020.00148
45.
SubramanianA, TamayoP, MoothaVK, et al.Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A, 2005; 102(43):15545–15550; doi: 10.1073/pnas.0506580102
46.
WongTH, DicksonFH, TimminsLR, et al.Tyrosine phosphorylation of tumor cell caveolin-1: Impact on cancer progression. Cancer Metastasis Rev, 2020; 39(2):455–469; doi: 10.1007/s10555-020-09892-9
47.
XiaoY, YuD. Tumor microenvironment as a therapeutic target in cancer. Pharmacol Ther, 2021; 221:107753; doi: 10.1016/j.pharmthera.2020.107753
48.
XuL, DengC, PangB, et al.TIP: A web server for resolving tumor immunophenotype profiling. Cancer Res, 2018; 78(23):6575–6580; doi: 10.1158/0008-5472.CAN-18-0689
49.
YoshiharaK, ShahmoradgoliM, MartínezE, et al.Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun, 2013; 4:2612; doi: 10.1038/ncomms3612
50.
YuG, WangL-G, HanY, et al.ClusterProfiler: An R package for comparing biological themes among gene clusters. OMICS, 2012; 16(5):284–287; doi: 10.1089/omi.2011.0118
51.
ZarembaA, EggermontAMM, RobertC, et al.The concepts of rechallenge and retreatment with immune checkpoint blockade in melanoma patients. Eur J Cancer, 2021; 155:268–280; doi: 10.1016/j.ejca.2021.07.002
52.
ZouW.Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol, 2006; 6(4):295–307; doi: 10.1038/nri1806
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