Relationship between PD-L1 expression and tumor stem cell marker CD44 as a promising basis for the development of new approaches to cancer targeted therapy

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Immunotherapy of malignant tumors is a rapidly developing area of oncology. PD-1 is a receptor expressed by activated T-lymphocytes. As a result of its interaction with the ligand (PD-L1 or PD-L2), the activity of T-lymphocytes is inhibited and their apoptosis occurs. Drugs that inhibit the interaction of PD-1 with ligands have an immunostimulatory effect and are effective in the treatment of many types of neoplasms: melanoma, lung cancer, bladder cancer, stomach cancer, various lymphomas, etc. However, response to this treatment is observed only in a narrow cohort of patients. To increase the effectiveness of immunotherapy, combined preparations and nanoparticles are being developed and created to enhance the effect of PD-L1 inhibitors, and containing hyaluronic acid as a ligand for the CD44 protein, which is expressed in many human tumors. However, the issue of co-expression of CD44 and PD-L1 remains poorly understood. This review is devoted to describing the features of co-expression and the mechanisms of interaction between CD44 and PD-L1. Promising directions for the development of new approaches to the immunotherapy of malignant tumors are presented.

Keywords:

PD-L1

immunotherapy of malignant tumors

cancer stem cell

Authors:

Sotnikova T.N.

I.V. Davydovsky City Clinical Hospital;
Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery

ORCID: 0000-0002-6482-1110

Malkov P.G.

I.V. Davydovsky City Clinical Hospital;
Lomonosov Moscow State University

ORCID: 0000-0001-7458-991X

Danilova N.V.

Lomonosov Moscow State University

SPIN RSCI: 6878-2025
Scopus AuthorID: 36613033400
ResearcherID: H-6477-2014
ORCID: 0000-0001-7848-6707

Received:

23.08.2023

Accepted:

20.09.2023

List of references:

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. https://doi.org/10.1038/nrc3239
Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384(9948):1109-1117. https://doi.org/10.1016/s0140-6736(14)60958-2
Zhang C, Wang H, Wang X, Zhao C, Wang H. CD44, a marker of cancer stem cells, is positively correlated with PD-L1 expression and immune cells infiltration in lung adenocarcinoma. Cancer Cell Int. 2020;20(1):583. https://doi.org/10.1186/s12935-020-01671-4
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489. https://doi.org/10.1038/nature10673
Bai R, Chen N, Li L, Du N, Bai L, Lv Z, Tian H, Cui J. Mechanisms of cancer resistance to immunotherapy. Front Oncol. 2020; 10:1290. https://doi.org/10.3389/fonc.2020.01290
Cho H, Matsumoto S, Fujita Y, Kuroda A, Menju T, Sonobe M, Kondo N, Torii I, Nakano T, Lara PN, et al. Trametinib plus 4-methylumbelliferone exhibits antitumor effects by ERK blockade and CD44 downregulation and affects PD-1 and PD-L1 in malignant pleural mesothelioma. J Thorac Oncol. 2017;12(3):477-490. https://doi.org/10.1016/j.jtho.2016.10.023
Lee YH, Yoon HY, Shin JM, Saravanakumar G, Noh KH, Song KH, Jeon JH, Kim DW, Lee KM, Kim K, et al. A polymeric conjugate foreignizing tumor cells for targeted immunotherapy in vivo. J Control Release. 2015;199:98-105. https://doi.org/10.1016/j.jconrel.2014.12.007
Shin JM, Oh SJ, Kwon S, Deepagan VG, Lee M, Song SH, Lee HJ, Kim S, Song KH, Kim TW, et al. A PEGylated hyaluronic acid conjugate for targeted cancer immunotherapy. J Control Release. 2017;267:181-190. https://doi.org/10.1016/j.jconrel.2017.08.032
Makrydimas G, Zagorianakou N, Zagorianakou P, Agnantis NJ. CD44 family and gynaecological cancer. In Vivo. 2003;17(6): 633-640.
Sleeman J, Moll J, Sherman L, Dall P, Pals ST, Ponta H, Herrlich P. The role of CD44 splice variants in human metastatic cancer. Ciba Found Symp. 1995;189:142-151; discussion 151-156, 174-176. https://doi.org/10.1002/9780470514719.ch11
Naor D, Sionov RV, Ish-Shalom D. CD44: structure, function, and association with the malignant process. Adv Cancer Res. 1997; 71:241-319. https://doi.org/10.1016/s0065-230x(08)60101-3
Xu H, Niu M, Yuan X, Wu K, Liu A. CD44 as a tumor biomarker and therapeutic target. Exp Hematol Oncol. 2020;9(1):36. https://doi.org/10.1186/s40164-020-00192-0
Hasegawa S. Extrapleural pneumonectomy or pleurectomy/decortication for malignant pleural mesothelioma. Gen Thorac Cardiovasc Surg. 2014;62(9):516-521. https://doi.org/10.1007/s11748-014-0389-7
Toole BP. Hyaluronan-CD44 interactions in cancer: paradoxes and possibilities. Clin Cancer Res. 2009;15(24):7462-7468. https://doi.org/10.1158/1078-0432.ccr-09-0479
Davidson B, Goldberg I, Gotlieb WH, Ben-Baruch G, Kopolovic J. CD44 expression in uterine cervical intraepithelial neoplasia and squamous cell carcinoma: an immunohistochemical study. Eur J Gynaecol Oncol. 1998;19(1):46-49.
Callagy G, O’Grady A, Butler D, Leader M, Kay E. Expression of CD44 in uterine cervical squamous neoplasia: a predictor of microinvasion? Gynecol Oncol. 2000;76(1):73-79. https://doi.org/10.1006/gyno.1999.5661
Brungs D, Lochhead A, Iyer A, Illemann M, Colligan P, Hirst NG, Splitt A, Liauw W, Vine KL, Pathmanandavel S, et al. Expression of cancer stem cell markers is prognostic in metastatic gastroesophageal adenocarcinoma. Pathology. 2019;51(5):474-480. https://doi.org/10.1016/j.pathol.2019.03.009
Kinugasa Y, Matsui T, Takakura N. CD44 expressed on cancer-associated fibroblasts is a functional molecule supporting the stemness and drug resistance of malignant cancer cells in the tumor microenvironment. Stem Cells. 2014;32(1):145-156. https://doi.org/10.1002/stem.1556
Lupia M, Cavallaro U. Ovarian cancer stem cells: still an elusive entity? Mol Cancer. 2017;16(1):64. https://doi.org/10.1186/s12943-017-0638-3
Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco SA, Calderon-Copete S, Pais Ferreira D, Carmona SJ, Scarpellino L, Gfeller D, Pradervand S, et al. Intratumoral Tcf1(+)PD-1(+)CD8(+) T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity. 2019;50(1):195-211.e10. https://doi.org/10.1016/j.immuni.2018.12.021
Yan Y, Zuo X, Wei D. Concise review: emerging role of CD44 in cancer stem cells: a promising biomarker and therapeutic target. Stem Cells Transl Med. 2015;4(9):1033-1043. https://doi.org/10.5966/sctm.2015-0048
Hou YC, Chao YJ, Hsieh MH, Tung HL, Wang HC, Shan YS. Low CD8+ T cell infiltration and high PD-L1 expression are associated with level of CD44+/CD133+ cancer stem cells and predict an unfavorable prognosis in pancreatic cancer. Cancers (Basel). 2019;11(4):541. https://doi.org/10.3390/cancers11040541
Alsuliman A, Colak D, Al-Harazi O, Fitwi H, Tulbah A, Al-Tweigeri T, Al-Alwan M, Ghebeh H. Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells. Mol Cancer. 2015;14:149. https://doi.org/10.1186/s12943-015-0421-2
Alwosaibai K, Aalmri S, Mashhour M, Ghandorah S, Alshangiti A, Azam F, Selwi W, Gharaibeh L, Alatawi Y, Alruwaii Z, et al. PD-L1 is highly expressed in ovarian cancer and associated with cancer stem cells populations expressing CD44 and other stem cell markers. BMC Cancer. 2023;23(1):13. https://doi.org/10.1186/s12885-022-10404-x
Lee Y, Shin JH, Longmire M, Wang H, Kohrt HE, Chang HY, Sunwoo JB. CD44+ cells in head and neck squamous cell carcinoma suppress T-cell-mediated immunity by selective constitutive and inducible expression of PD-L1. Clin Cancer Res. 2016;22(14):3571-3581. https://doi.org/10.1158/1078-0432.ccr-15-2665
Wei F, Zhang T, Deng SC, Wei JC, Yang P, Wang Q, Chen ZP, Li WL, Chen HC, Hu H, et al. PD-L1 promotes colorectal cancer stem cell expansion by activating HMGA1-dependent signaling pathways. Cancer Lett. 2019;450:1-13. https://doi.org/10.1016/j.canlet.2019.02.022
Moutafi MK, Molero M, Martinez Morilla S, Baena J, Vathiotis IA, Gavrielatou N, Castro-Labrador L, de Garibay GR, Adradas V, Orive D, et al. Spatially resolved proteomic profiling identifies tumor cell CD44 as a biomarker associated with sensitivity to PD-1 axis blockade in advanced non-small-cell lung cancer. J Immunother Cancer. 2022;10(8):e004757. https://doi.org/10.1136/jitc-2022-004757
Unver N, Tavukcuoglu E, Esendagli G. Tailored modulation of stemness and drug resistance marker characteristics in K-Ras mutant lung cancer cells via PD-L1 gene suppression. Life Sci. 2022;311(Pt B):121171. https://doi.org/10.1016/j.lfs.2022.121171
Kong T, Ahn R, Yang K, Zhu X, Fu Z, Morin G, Bramley R, Cliffe NC, Xue Y, Kuasne H, et al. CD44 promotes PD-L1 expression and its tumor-intrinsic function in breast and lung cancers. Cancer Res. 2020;80(3):444-457. https://doi.org/10.1158/0008-5472.CAN-19-1108
De Falco V, Tamburrino A, Ventre S, Castellone MD, Malek M, Manié SN, Santoro M. CD44 proteolysis increases CREB phosphorylation and sustains proliferation of thyroid cancer cells. Cancer Res. 2012;72(6):1449-1458. https://doi.org/10.1158/0008-5472.CAN-11-3320
Okamoto I, Kawano Y, Murakami D, Sasayama T, Araki N, Miki T, Wong AJ, Saya H. Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway. J Cell Biol. 2001;155(5):755-762. https://doi.org/10.1083/jcb.200108159
Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007;11(3):259-273. https://doi.org/10.1016/j.ccr.2007.01.013
Zhang G, Guo L, Yang C, Liu Y, He Y, Du Y, Wang W, Gao F. A novel role of breast cancer-derived hyaluronan on inducement of M2-like tumor-associated macrophages formation. Oncoimmunology. 2016;5(6):e1172154. https://doi.org/10.1080/2162402x.2016.1172154
Black M, Barsoum IB, Truesdell P, Cotechini T, Macdonald-Goodfellow SK, Petroff M, Siemens DR, Koti M, Craig AW, Graham CH. Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis. Oncotarget. 2016;7(9):10557-10567. https://doi.org/10.18632/oncotarget.7235
Haegel-Kronenberger H, de la Salle H, Bohbot A, Galon J, Tartour E, Cazenave JP, Hanau D. Regulation of CD44 isoform expression and CD44-mediated signaling in human dendritic cells. Adv Exp Med Biol. 1997;417:83-90. https://doi.org/10.1007/978-1-4757-9966-8_14
Yang M, Liu Y, Ren G, Shao Q, Gao W, Sun J, Wang H, Ji C, Li X, Zhang Y, et al. Increased expression of surface CD44 in hypoxia-DCs skews helper T cells toward a Th2 polarization. Sci Rep. 2015;5:13674. https://doi.org/10.1038/srep13674
Mattheolabakis G, Milane L, Singh A, Amiji MM. Hyaluronic acid targeting of CD44 for cancer therapy: from receptor biology to nanomedicine. J Drug Target. 2015;23(7-8):605-618. https://doi.org/10.3109/1061186x.2015.1052072
Cheng Y, Wang C, Wang H, Zhang Z, Yang X, Dong Y, Ma L, Luo J. Combination of an autophagy inhibitor with immunoadjuvants and an anti-PD-L1 antibody in multifunctional nanoparticles for enhanced breast cancer immunotherapy. BMC Med. 2022; 20(1):411. https://doi.org/10.1186/s12916-022-02614-8
Kim S, Heo R, Song SH, Song KH, Shin JM, Oh SJ, Lee HJ, Chung JE, Park JH, Kim TW. PD-L1 siRNA-hyaluronic acid conjugate for dual-targeted cancer immunotherapy. J Control Release. 2022;346:226-239. https://doi.org/10.1016/j.jconrel.2022.04.023
Lee JC, Wu ATH, Chen JH, Huang WY, Lawal B, Mokgautsi N, Huang HS, Ho CL. HNC0014, a multi-targeted small-molecule, inhibits head and neck squamous cell carcinoma by suppressing c-Met/STAT3/CD44/PD-L1 oncoimmune signature and eliciting antitumor immune responses. Cancers (Basel). 2020;12(12):3759. https://doi.org/10.3390/cancers12123759
Sun F, Zhu Q, Li T, Saeed M, Xu Z, Zhong F, Song R, Huai M, Zheng M, Xie C, et al. Regulating glucose metabolism with prodrug nanoparticles for promoting photoimmunotherapy of pancreatic cancer. Adv Sci (Weinh). 2021;8(4):2002746. https://doi.org/10.1002/advs.202002746
Rios de la Rosa JM, Pingrajai P, Pelliccia M, Spadea A, Lallana E, Gennari A, Stratford IJ, Rocchia W, Tirella A, Tirelli N. Binding and internalization in receptor-targeted carriers: the complex role of CD44 in the uptake of hyaluronic acid-based nanoparticles (siRNA delivery). Adv Healthc Mater. 2019;8(24):e1901182. https://doi.org/10.1002/adhm.201901182
Qian L, Liu F, Chu Y, Zhai Q, Wei X, Shao J, Li R, Xu Q, Yu L, Liu B, et al. MicroRNA-200c nanoparticles sensitized gastric cancer cells to radiotherapy by regulating PD-L1 expression and EMT. Cancer Manag Res. 2020;12:12215-12223. https://doi.org/10.2147/cmar.s279978
Wang X, Gao J, Li C, Xu C, Li X, Meng F, Liu Q, Wang Q, Yu L, Liu B, et al. In situ gelatinase-responsive and thermosensitive nanocomplex for local therapy of gastric cancer with peritoneal metastasis. Mater Today Bio. 2022;15:100305. https://doi.org/10.1016/j.mtbio.2022.100305

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