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Current Gene Therapy

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ISSN (Print): 1566-5232
ISSN (Online): 1875-5631

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HCST Expression Distinguishes Immune-hot and Immune-cold Subtypes in Pancreatic Ductal Adenocarcinoma

Author(s): Boyi Ma, Dai-jun Zhang, Yabin Hu, Xianghan Chen, Ruining Gong, Ke Lei, Qian Yu* and He Ren*
Published on: 20 June, 2024

DOI: 10.2174/1566523223666230720101531

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Abstract

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent malignancy of the pancreas, and the incidence of this disease is approximately equivalent to the mortality rate. Immunotherapy has made a remarkable breakthrough in numerous cancers, while its efficacy in PDAC remains limited due to the immunosuppressive microenvironment. Immunotherapy efficacy is highly correlated with the abundance of immune cells, particularly cytotoxic T cells. Therefore, molecular classifier is needed to identify relatively hot tumors that may benefit from immunotherapy.

Method: In this study, we carried out a transcriptome analysis of 145 pancreatic tumors to define the underlying immune regulatory mechanism driving the PDAC immunosuppressive microenvironment. The immune subtype was identified by consensus clustering, and the underlying PDAC immune activation mechanism was thoroughly examined using single sample gene set enrichment analysis (ssGSEA). Area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to assess the accuracy of the molecular classifier in differentiating immunological subgroups of PDAC.5

Result: The protein level of molecular classifier was verified by immunohistochemistry in human PDAC tissue. Immune-hot tumors displayed higher levels of immune cell infiltration and immune checkpoint, in line with enriched immune escape pathways. Hematopoietic cell signal transducer (HCST), a molecular classifier used to differentiate immunological subtypes of PDAC, has shown a substantial link with the expression levels of cytotoxic markers, such as CD8A and CD8B. At the single cell level, we found that HCST was predominantly expressed in CD8T cells. By immunohistochemistry and survival analysis, we further demonstrated the prognostic value of HCST in PDAC.

Conclusion: We identified HCST as a molecular classifier to distinguish PDAC immune subtypes, which may be useful for early diagnosis and targeted therapy of PDAC.

[1]
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023; 73(1): 17-48.
[http://dx.doi.org/10.3322/caac.21763] [PMID: 36633525]
[2]
Li YJ, Wu JY, Wang JM, Xiang DX. Emerging nanomedicine-based strategies for preventing metastasis of pancreatic cancer. J Control Release 2020; 320: 105-11.
[http://dx.doi.org/10.1016/j.jconrel.2020.01.041] [PMID: 31978441]
[3]
Wolfgang CL, Herman JM, Laheru DA, et al. Recent progress in pancreatic cancer. CA Cancer J Clin 2013; 63(5): 318-48.
[http://dx.doi.org/10.3322/caac.21190] [PMID: 23856911]
[4]
Wenming W, Gang J, Chunyou W. The current surgical treatment of pancreatic cancer in China: A national wide cross-sectional study. J Pancreatol 2019; 2(1): 16-21.
[5]
McBride A, Bonafede M, Cai Q, et al. Comparison of treatment patterns and economic outcomes among metastatic pancreatic cancer patients initiated on nab -paclitaxel plus gemcitabine versus FOLFIRINOX. Expert Rev Clin Pharmacol 2017; 10(10): 1153-60.
[http://dx.doi.org/10.1080/17512433.2017.1365598] [PMID: 28795609]
[6]
Kang J, Hwang I, Yoo C, et al. Nab-paclitaxel plus gemcitabine versus FOLFIRINOX as the first-line chemotherapy for patients with metastatic pancreatic cancer: Retrospective analysis. Invest New Drugs 2018; 36(4): 732-41.
[http://dx.doi.org/10.1007/s10637-018-0598-5] [PMID: 29616439]
[7]
Shimpei M, Michiaki U, Jun Y. Adjuvant and neoadjuvant therapy for pancreatic cancer. J Pancreatol 2019; 2(3): 100-6.
[8]
Leonhardt CS, Traub B. Adjuvant and neoadjuvant chemotherapy in pancreatic ductal adenocarcinoma. J Pancreatol 2020; 2020: 1-11.
[9]
Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366(26): 2455-65.
[http://dx.doi.org/10.1056/NEJMoa1200694] [PMID: 22658128]
[10]
Gao Y, Chen S, Vafaei S, Zhong X. Tumor-infiltrating immune cell signature predicts the prognosis and chemosensitivity of patients with pancreatic ductal adenocarcinoma. Front Oncol 2020; 10: 557638.
[http://dx.doi.org/10.3389/fonc.2020.557638] [PMID: 33102222]
[11]
Iorio V, Rosati A, D’Auria R, et al. Combined effect of anti-BAG3 and anti-PD-1 treatment on macrophage infiltrate, CD8+ T cell number and tumour growth in pancreatic cancer. Gut 2018; 67(4): 780-2.
[PMID: 28801350]
[12]
Ren B, Cui M, Yang G, et al. Tumor microenvironment participates in metastasis of pancreatic cancer. Mol Cancer 2018; 17(1): 108.
[http://dx.doi.org/10.1186/s12943-018-0858-1] [PMID: 30060755]
[13]
Principe DR, Korc M, Kamath SD, Munshi HG, Rana A. Trials and tribulations of pancreatic cancer immunotherapy. Cancer Lett 2021; 504: 1-14.
[http://dx.doi.org/10.1016/j.canlet.2021.01.031] [PMID: 33549709]
[14]
Shi J, Lu P, Shen W, et al. CD90 highly expressed population harbors a stemness signature and creates an immunosuppressive niche in pancreatic cancer. Cancer Lett 2019; 453: 158-69.
[http://dx.doi.org/10.1016/j.canlet.2019.03.051] [PMID: 30954649]
[15]
Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010; 33(8): 828-33.
[http://dx.doi.org/10.1097/CJI.0b013e3181eec14c] [PMID: 20842054]
[16]
Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515(7528): 563-7.
[http://dx.doi.org/10.1038/nature14011] [PMID: 25428504]
[17]
Le DT, Lutz E, Uram JN, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother 2013; 36(7): 382-9.
[http://dx.doi.org/10.1097/CJI.0b013e31829fb7a2] [PMID: 23924790]
[18]
Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016; 531(7592): 47-52.
[http://dx.doi.org/10.1038/nature16965] [PMID: 26909576]
[19]
Danilova L, Ho WJ, Zhu Q, et al. Programmed cell death ligand-1 (PD-L1) and CD8 expression profiling identify an immunologic subtype of pancreatic ductal adenocarcinomas with favorable survival. Cancer Immunol Res 2019; 7(6): 886-95.
[http://dx.doi.org/10.1158/2326-6066.CIR-18-0822] [PMID: 31043417]
[20]
Sakaguchi M, Murata H, Aoyama Y, et al. DNAX-activating protein 10 (DAP10) membrane adaptor associates with receptor for advanced glycation end products (RAGE) and modulates the RAGE-triggered signaling pathway in human keratinocytes. J Biol Chem 2014; 289(34): 23389-402.
[http://dx.doi.org/10.1074/jbc.M114.573071] [PMID: 25002577]
[21]
Hernández-Caselles T, Miguel RCS, Ruiz-Alcaraz AJ, García-Peñarrubia P. CD33 (Siglec-3) inhibitory function: Role in the NKG2D/DAP10 activating pathway. J Immunol Res 2019; 2019: 1-15.
[http://dx.doi.org/10.1155/2019/6032141] [PMID: 31143782]
[22]
Zheng L, Ren L, Kouhi A, et al. A humanized lym-1 CAR with novel DAP10/DAP12 signaling domains demonstrates reduced tonic signaling and increased antitumor activity in B-cell lymphoma models. Clin Cancer Res 2020; 26(14): 3694-706.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-3417] [PMID: 32273277]
[23]
Li M, Zhi L, Yin M, et al. A novel bispecific chimeric PD1-DAP10/NKG2D receptor augments NK92-cell therapy efficacy for human gastric cancer SGC-7901 cell. Biochem Biophys Res Commun 2020; 523(3): 745-52.
[http://dx.doi.org/10.1016/j.bbrc.2020.01.005] [PMID: 31952789]
[24]
Qi X, Qi C, Wu T, Hu Y. CSF1R and HCST: Novel candidate biomarkers predicting the response to immunotherapy in non-small cell lung cancer. Technol Cancer Res Treat 2020; 19.
[http://dx.doi.org/10.1177/1533033820970663] [PMID: 33153411]
[25]
Zhou Y, Wang X, Zhang W, et al. The immune-related gene HCST as a novel biomarker for the diagnosis and prognosis of clear cell renal cell carcinoma. Front Oncol 2021; 11: 630706.
[http://dx.doi.org/10.3389/fonc.2021.630706] [PMID: 33968730]
[26]
Wang W, Li S, Lin J, et al. The roles and potential mechanisms of HCST in the prognosis and immunity of KIRC via comprehensive analysis. Am J Transl Res 2022; 14(2): 752-71.
[PMID: 35273683]
[27]
Moffitt RA, Marayati R, Flate EL, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet 2015; 47(10): 1168-78.
[http://dx.doi.org/10.1038/ng.3398] [PMID: 26343385]
[28]
Steele NG, Carpenter ES, Kemp SB, et al. Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer. Nat Can 2020; 1(11): 1097-112.
[http://dx.doi.org/10.1038/s43018-020-00121-4] [PMID: 34296197]
[29]
Yoshihara K, Shahmoradgoli M, Martínez E, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 2013; 4(1): 2612.
[http://dx.doi.org/10.1038/ncomms3612] [PMID: 24113773]
[30]
Aran D, Hu Z, Butte AJ. xCell: Digitally portraying the tissue cellular heterogeneity landscape. Genome Biol 2017; 18(1): 220.
[http://dx.doi.org/10.1186/s13059-017-1349-1] [PMID: 29141660]
[31]
Wilkerson MD, Hayes DN. ConsensusClusterPlus: A class discovery tool with confidence assessments and item tracking. Bioinformatics 2010; 26(12): 1572-3.
[http://dx.doi.org/10.1093/bioinformatics/btq170] [PMID: 20427518]
[32]
Gaujoux R, Seoighe C. A flexible R package for nonnegative matrix factorization. BMC Bioinformatics 2010; 11(1): 367.
[http://dx.doi.org/10.1186/1471-2105-11-367] [PMID: 20598126]
[33]
Hänzelmann S, Castelo R, Guinney J. GSVA: Gene set variation analysis for microarray and RNA-Seq data. BMC Bioinformatics 2013; 14(1): 7.
[http://dx.doi.org/10.1186/1471-2105-14-7] [PMID: 23323831]
[34]
Barbie DA, Tamayo P, Boehm JS, et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 2009; 462(7269): 108-12.
[http://dx.doi.org/10.1038/nature08460] [PMID: 19847166]
[35]
Seckinger A, Meißner T, Moreaux J, et al. Clinical and prognostic role of annexin A2 in multiple myeloma. Blood 2012; 120(5): 1087-94.
[http://dx.doi.org/10.1182/blood-2012-03-415588] [PMID: 22705595]
[36]
Hao Y, Hao S, Andersen-Nissen E, et al. Integrated analysis of multimodal single-cell data. Cell 2021; 184(13): 3573-3587.e29.
[http://dx.doi.org/10.1016/j.cell.2021.04.048] [PMID: 34062119]
[37]
Lall S, Sinha D, Bandyopadhyay S, Sengupta D. Structure-aware principal component analysis for single-cell RNA-seq data. J Comput Biol 2018; 25(12): 1365-73.
[http://dx.doi.org/10.1089/cmb.2018.0027] [PMID: 30133312]
[38]
Satija R, Farrell JA, Gennert D, Schier AF, Regev A. Spatial reconstruction of single-cell gene expression data. Nat Biotechnol 2015; 33(5): 495-502.
[http://dx.doi.org/10.1038/nbt.3192] [PMID: 25867923]
[39]
Aran D, Looney AP, Liu L, et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol 2019; 20(2): 163-72.
[http://dx.doi.org/10.1038/s41590-018-0276-y] [PMID: 30643263]
[40]
Cao L, Huang C, Cui Zhou D, et al. Proteogenomic characterization of pancreatic ductal adenocarcinoma. Cell 2021; 184(19): 5031-5052.e26.
[http://dx.doi.org/10.1016/j.cell.2021.08.023] [PMID: 34534465]
[41]
Chen Z, Wang Y, Fong WP, et al. A quantitative score of immune cell infiltration predicts the prognosis in pancreatic ductal adenocarcinoma. Int Immunopharmacol 2021; 98: 107890.
[http://dx.doi.org/10.1016/j.intimp.2021.107890] [PMID: 34174701]
[42]
Klein D. The Tumor Vascular Endothelium as Decision Maker in Cancer Therapy. Front Oncol 2018; 8: 367.
[http://dx.doi.org/10.3389/fonc.2018.00367] [PMID: 30250827]
[43]
Schaaf MB, Garg AD, Agostinis P. Defining the role of the tumor vasculature in antitumor immunity and immunotherapy. Cell Death Dis 2018; 9(2): 115.
[http://dx.doi.org/10.1038/s41419-017-0061-0] [PMID: 29371595]
[44]
Qian J, Wang C, Wang B, et al. The IFN-γ/PD-L1 axis between T cells and tumor microenvironment: Hints for glioma anti-PD-1/PD-L1 therapy. J Neuroinflammation 2018; 15(1): 290.
[http://dx.doi.org/10.1186/s12974-018-1330-2] [PMID: 30333036]
[45]
Li R, He Y, Zhang H, et al. Identification and validation of immune molecular subtypes in pancreatic ductal adenocarcinoma: Implications for prognosis and immunotherapy. Front Immunol 2021; 12: 690056.
[http://dx.doi.org/10.3389/fimmu.2021.690056] [PMID: 34335594]
[46]
Hyka-Nouspikel N, Phillips JH. Physiological roles of murine DAP10 adapter protein in tumor immunity and autoimmunity. Immunol Rev 2006; 214(1): 106-17.
[http://dx.doi.org/10.1111/j.1600-065X.2006.00456.x] [PMID: 17100879]
[47]
Li TJ, Jin KZ, Li H, et al. SIGLEC15 amplifies immunosuppressive properties of tumor-associated macrophages in pancreatic cancer. Cancer Lett 2022; 530: 142-55.
[http://dx.doi.org/10.1016/j.canlet.2022.01.026] [PMID: 35077803]
[48]
Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 2008; 8(7): 533-44.
[http://dx.doi.org/10.1038/nri2356] [PMID: 18551128]
[49]
Fujiwara T, Yakoub MA, Chandler A, et al. CSF1/CSF1R signaling inhibitor pexidartinib (PLX3397) reprograms tumor-associated macrophages and stimulates T-cell infiltration in the sarcoma microenvironment. Mol Cancer Ther 2021; 20(8): 1388-99.
[http://dx.doi.org/10.1158/1535-7163.MCT-20-0591] [PMID: 34088832]
[50]
Girardi M, Oppenheim DE, Steele CR, et al. Regulation of cutaneous malignancy by gammadelta T cells. Science 2001; 294(5542): 605-9.
[http://dx.doi.org/10.1126/science.1063916] [PMID: 11567106]
[51]
Cerwenka A, Baron JL, Lanier LL. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc Natl Acad Sci USA 2001; 98(20): 11521-6.
[http://dx.doi.org/10.1073/pnas.201238598] [PMID: 11562472]

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