Differentiation of cancer cells upregulates HLA‑G and PD‑L1

Ullah,Matti; Meziani,Sarah; Shah,Shahid; Kaci,Rachid; Pimpie,Cynthia; Pocard,Marc; Mirshahi,Massoud

doi:10.3892/or.2020.7572

Differentiation of cancer cells upregulates HLA‑G and PD‑L1

Authors:
- Matti Ullah
- Sarah Meziani
- Shahid Shah
- Rachid Kaci
- Cynthia Pimpie
- Marc Pocard
- Massoud Mirshahi
View Affiliations

Affiliations: CAP‑Paris Tech., INSERM U1275, Lariboisière Hospital, 75010 Paris, France
Published online on: April 1, 2020 https://doi.org/10.3892/or.2020.7572
Pages: 1797-1804
Copyright: © Ullah 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

A tumor contains special types of cells that have characteristics similar to stem cells that aid in tumor initiation, evasion and proliferation and are often resistant to chemotherapy. These cancer stem cells can be differentiated to eradicate their stemness and proliferative capacity by differentiating agents. This study investigated the effect of differentiation on the expression of two immune checkpoint inhibitors, human leukocyte antigen‑G (HLA‑G) and programmed death ligand‑1 (PD‑L1). Two cancer cell lines (OVCAR‑3‑NIH and KATO‑III) were treated with adipocyte and neurocyte differentiation media for 14 days. Bone‑marrow derived mesenchymal stem cells (BM‑MSCs) were used as control healthy stem cells. We found that the cancer cell lines (OVCAR‑3‑NIH and KATO‑III) when subjected to differentiation lost their proliferation ability. BM‑MSC proliferation was not halted but was decreased in the adipocyte differentiation media. There was no decrease in the CD90 stem cell marker in the BM‑MSCs; however, both cancer cell lines showed decreased CD90 stem cell marker. A significant increase in HLA‑G was noted for both the cancer cell lines following adipocyte differentiation. No effect was found for BM‑MSCs. Moreover, an increase in PD‑L1 in cancer cell lines was found following neurocyte differentiation. Moreover, we found that differentiation resulted in decreased PD‑L1 expression in BM‑MSCs. Differentiation therapy of cancer stem cells may result in increased immunosuppression ability, hence causing hindrance in the removal of cancer cells. Moreover, the differentiation of healthy stem cells can result in increased immunogenic reactivity owing to a decrease in PD‑L1 expression.

View Figures

View References

1	Yan M and Liu Q: Differentiation therapy: A promising strategy for cancer treatment. Chin J Cancer. 35:32016. View Article : Google Scholar : PubMed/NCBI
2	Vinogradov S and Wei X: Cancer stem cells and drug resistance: The potential of nanomedicine. Nanomedicine (Lond). 7:597–615. 2012. View Article : Google Scholar : PubMed/NCBI
3	Codony-Servat J and Rosell R: Cancer stem cells and immunoresistance: Clinical implications and solutions. Transl Lung Cancer Res. 4:689–703. 2015.PubMed/NCBI
4	Sultan M, Coyle KM, Vidovic D, Thomas ML, Gujar S and Marcato P: Hide-and-seek: The interplay between cancer stem cells and the immune system. Carcinogenesis. 38:107–118. 2017. View Article : Google Scholar : PubMed/NCBI
5	Lee Y and Sunwoo J: PD-L1 is preferentially expressed on CD44⁺ tumor-initiating cells in head and neck squamous cell carcinoma. J Immunother Cancer. 2 (Suppl):2702014. View Article : Google Scholar
6	Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 366:2455–2465. 2012. View Article : Google Scholar : PubMed/NCBI
7	LeMaoult J, Caumartin J, Daouya M, Favier B, Le Rond S, Gonzalez A and Carosella ED: Immune regulation by pretenders: Cell-to-cell transfers of HLA-G make effector T cells act as regulatory cells. Blood. 109:2040–2048. 2007. View Article : Google Scholar : PubMed/NCBI
8	Ullah M, Azazzen D, Kaci R, Benabbou N, Pujade Lauraine E, Pocard M and Mirshahi M: High expression of HLA-G in ovarian carcinomatosis: The role of interleukin-1β. Neoplasia. 21:331–342. 2019. View Article : Google Scholar : PubMed/NCBI
9	Yie SM, Yang H, Ye SR, Li K, Dong DD and Lin XM: Expression of human leucocyte antigen G (HLA-G) is associated with prognosis in non-small cell lung cancer. Lung Cancer. 58:267–274. 2007. View Article : Google Scholar : PubMed/NCBI
10	Cai MB, Han HQ, Bei JX, Liu CC, Lei JJ, Cui Q, Feng QS, Wang HY, Zhang JX, Liang Y, et al: Expression of human leukocyte antigen G is associated with prognosis in nasopharyngeal carcinoma. Int J Biol Sci. 8:891–900. 2012. View Article : Google Scholar : PubMed/NCBI
11	Kirana C, Ruszkiewicz A, Stubbs RS, Hardingham JE, Hewett PJ, Maddern GJ and Hauben E: Soluble HLA-G is a differential prognostic marker in sequential colorectal cancer disease stages. Int J Cancer. 140:2577–2586. 2017. View Article : Google Scholar : PubMed/NCBI
12	Tang Y, Fang W, Zhang Y, Hong S, Kang S, Yan Y, Chen N, Zhan J, He X, Qin T, et al: The association between PD-L1 and EGFR status and the prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFR-TKIs. Oncotarget. 6:14209–14219. 2015. View Article : Google Scholar : PubMed/NCBI
13	Inamura K, Yokouchi Y, Sakakibara R, Kobayashi M, Subat S, Ninomiya H, Nagano H, Nomura K, Okumura S and Ishikawa Y: Relationship of tumor PD-L1 expression with EGFR wild-type status and poor prognosis in lung adenocarcinoma. Jpn J Clin Oncol. 46:935–941. 2016. View Article : Google Scholar : PubMed/NCBI
14	Mu CY, Huang JA, Chen Y, Chen C and Zhang XG: High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol. 28:682–688. 2011. View Article : Google Scholar : PubMed/NCBI
15	Xiang X, Yu PC, Long D, Liao XL, Zhang S, You XM, Zhong JH and Li LQ: Prognostic value of PD-L1 expression in patients with primary solid tumors. Oncotarget. 9:5058–5072. 2017.PubMed/NCBI
16	Sorensen SF, Zho W, Dolled-Filhart M, Georgsen JB, Wang Z, Emancipator K, Wu D, Busch-Sørensen M, Meldgaard P and Hager H: PD-L1 expression and survival among patients with advanced non-small cell lung cancer treated with chemotherapy. Transl Oncol. 9:64–69. 2016. View Article : Google Scholar : PubMed/NCBI
17	Gu L, Chen M, Guo D, Zhu H, Zhang W, Pan J, Zhong X, Li X, Qian H and Wang X: PD-L1 and gastric cancer prognosis: A systematic review and meta-analysis. PLoS One. 12:e01826922017. View Article : Google Scholar : PubMed/NCBI
18	Grignani F, Ferrucci PF, Testa U, Talamo G, Fagioli M, Alcalay M, Mencarelli A, Grignani F, Peschle C, Nicoletti I, et al: The acute promyelocytic leukemia-specific PML-RARα fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell. 74:423–431. 1993. View Article : Google Scholar : PubMed/NCBI
19	Su M, Alonso S, Jones JW, Yu J, Kane MA, Jones RJ and Ghiaur G: All-trans retinoic acid activity in acute myeloid leukemia: Role of cytochrome P450 enzyme expression by the microenvironment. PLoS One. 10:e01277902015. View Article : Google Scholar : PubMed/NCBI
20	Shah S, Pocard M and Mirshahi M: Targeting the differentiation of gastric cancer cells (KATO-III) downregulates epithelial-mesenchymal and cancer stem cell markers. Oncol Rep. 42:670–678. 2019.PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Eaves CJ: Cancer stem cells: Here, there, everywhere? Nature. 456:581–582. 2008. View Article : Google Scholar : PubMed/NCBI
23	Kawamata H, Tachibana M, Fujimori T and Imai Y: Differentiation-inducing therapy for solid tumors. Curr Pharm Des. 12:379–385. 2006. View Article : Google Scholar : PubMed/NCBI
24	Kaci R, Shahid S, Réa L, Philipe B, Amu T, Marc P and Massoud MJII: Neural signature expressed by cells from ovarian carcinoma (A Case Report). J Immunochem Immunopathol. 1:22015.
25	Montespan F, Deschaseaux F, Sensébé L, Carosella ED and Rouas-Freiss N: Osteodifferentiated mesenchymal stem cells from bone marrow and adipose tissue express HLA-G and display immunomodulatory properties in HLA-mismatched settings: Implications in bone repair therapy. J Immunol Res. 2014:2303462014. View Article : Google Scholar : PubMed/NCBI
26	Veldhuis-Vlug AG and Rosen CJ: Clinical implications of bone marrow adiposity. J Intern Med. 283:121–139. 2018. View Article : Google Scholar : PubMed/NCBI
27	Islam A: Do bone marrow fat cells or their precursors have a pathogenic role in idiopathic aplastic anaemia? Med Hypotheses. 25:209–217. 1988. View Article : Google Scholar : PubMed/NCBI
28	Lu W, Weng W, Zhu Q, Zhai Y, Wan Y, Liu H, Yang S, Yu Y, Wei Y and Shi J: Small bone marrow adipocytes predict poor prognosis in acute myeloid leukemia. Haematologica. 103:e21–e24. 2018. View Article : Google Scholar : PubMed/NCBI