PD‑L1 expression levels on tumor cells affect their immunosuppressive activity

Zheng,Yang; Fang,You‑Chen; Li,Jing

doi:10.3892/ol.2019.10903

PD‑L1 expression levels on tumor cells affect their immunosuppressive activity

Authors:
- Yang Zheng
- You‑Chen Fang
- Jing Li
View Affiliations

Affiliations: Chinese Academy of Sciences Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China
Published online on: September 20, 2019 https://doi.org/10.3892/ol.2019.10903
Pages: 5399-5407
Copyright: © Zheng 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

Programmed cell death 1 (PD‑1) is an immuno‑checkpoint receptor which is primarily expressed on T cells, monocytes, natural killer cells and macrophages. Programmed death‑ligand 1 (PD‑L1) is the primary ligand of PD‑1 and is constitutively expressed on antigen presenting cells, mesenchymal stem cells and bone marrow‑derived mast cells. In addition, PD‑L1 is also expressed on a wide range of tumor cells, including lung cancer, breast cancer and melanoma. PD‑1 and PD‑L1 are important members of the immunoglobulin super‑family and participate in immune regulation. In the present study, the immune‑suppressive effects of a number of tumor cell lines were determined. The breast tumor cell lines MCF‑7 and MDA‑MB‑231 displayed the largest inhibitory effects on T‑cell activation and cytokine secretion in a co‑culture system. The HepG2, A549 and A375 cells displayed limited inhibitory effects. MCF‑7 and MDA‑MB‑231 cells expressed the highest level of PD‑L1 among the cells used, which may explain their higher immuno‑suppressive effects. Compound A0‑L, a small molecule inhibitor of the PD‑1/PD‑L1 interaction, restored T cell functions. Additionally, it was demonstrated that the tumor cells with higher levels of PD‑L1 expression suppressed signaling pathways involved in T‑cell activation, such as the T‑cell receptor‑ zeta chain of T cell receptor associated protein kinase ZAP70‑RAS‑GTPase‑extracellular‑signal‑regulated kinases and CD28‑PI3K‑Akt serine/threonine kinases pathways. These findings suggest that tumor cells with higher expression levels of PD‑L1 may exhibit higher immuno‑suppressive activity, and that drugs targeting the PD‑1/PD‑L1 interaction may have improved therapeutic effects on tumors expressing higher levels of PD‑L1.

View Figures

View References

1	Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE and Rosenberg SA: Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 114:1537–1544. 2009. View Article : Google Scholar : PubMed/NCBI
2	Prosser ME, Brown CE, Shami AF, Forman SJ and Jensen MC: Tumor PD-L1 co-stimulates primary human CD8(+) cytotoxic T cells modified to express a PD1:CD28 chimeric receptor. Mol Immunol. 51:263–272. 2012. View Article : Google Scholar : PubMed/NCBI
3	June CH, Ledbetter JA, Linsley PS and Thompson CB: Role of the CD28 receptor in T-cell activation. Immunol Today. 11:211–216. 1990. View Article : Google Scholar : PubMed/NCBI
4	Alvarez-Vallina L and Hawkins RE: Antigen-specific targeting of CD28-mediated T cell co-stimulation using chimeric single-chain antibody variable fragment-CD28 receptors. Eur J Immunol. 26:2304–2309. 1996. View Article : Google Scholar : PubMed/NCBI
5	Louis-Dit-Sully C, Blumenthal B, Duchniewicz M, Beck-Garcia K, Fiala GJ, Beck-García E, Mukenhirn M, Minguet S and Schamel WW: Activation of the TCR complex by peptide-MHC and superantigens. Exs. 104:9–23. 2014.PubMed/NCBI
6	Salazar-Fontana LI, Barr V, Samelson LE and Bierer BE: CD28 engagement promotes actin polymerization through the activation of the small Rho GTPase Cdc42 in human T cells. J Immunol. 171:2225–2232. 2003. View Article : Google Scholar : PubMed/NCBI
7	Passardi A, Canale M, Valgiusti M and Ulivi P: Immune checkpoints as a target for colorectal cancer treatment. Int J Mol Sci. 18(pii): E13242017. View Article : Google Scholar : PubMed/NCBI
8	Saad FT, Hincal E and Kaymakamzade B: Dynamics of immune checkpoints, immune system, and BCG in the treatment of superficial bladder cancer. Comput Math Methods Med. 2017:35730822017. View Article : Google Scholar : PubMed/NCBI
9	Sharma P and Allison JP: Immune checkpoint targeting in cancer therapy: Toward combination strategies with curative potential. Cell. 161:205–214. 2015. View Article : Google Scholar : PubMed/NCBI
10	Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012. View Article : Google Scholar : PubMed/NCBI
11	Beatty GL and Gladney WL: Immune Escape Mechanisms as a Guide for Cancer Immunotherapy. Clin Cancer Res. 21:687–692. 2015. View Article : Google Scholar : PubMed/NCBI
12	Janssen LME, Ramsay EE, Logsdon CD and Overwijk WW: The immune system in cancer metastasis: Friend or foe? J Immunother Cancer. 5:792017. View Article : Google Scholar : PubMed/NCBI
13	Bartelt RR, Cruz-Orcutt N, Collins M and Houtman JC: Comparison of T cell receptor-induced proximal signaling and downstream functions in immortalized and primary T cells. PLoS One. 4:e54302009. View Article : Google Scholar : PubMed/NCBI
14	Thaker YR, Schneider H and Rudd CE: TCR and CD28 activate the transcription factor NF-κB in T-cells via distinct adaptor signaling complexes. Immunol Lett. 163:113–119. 2015. View Article : Google Scholar : PubMed/NCBI
15	Dong H, Zhu G, Tamada K and Chen L: B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 5:1365–1369. 1999. View Article : Google Scholar : PubMed/NCBI
16	Latchman Y, Wood C, Chemova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, et al: PD-L2, a novel B7 homologue, is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 15:261–268. 2001. View Article : Google Scholar
17	Kim HR, Ha SJ, Hong MH, Heo SJ, Koh YW, Choi EC, Kim EK, Pyo KH, Jung I, Seo D, et al: PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients. Sci Rep. 6:369562016. View Article : Google Scholar : PubMed/NCBI
18	Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, Koulmanda M, Freeman GJ, Sayegh MH and Sharpe AH: Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 203:883–895. 2006. View Article : Google Scholar : PubMed/NCBI
19	Butte MJ, Keir ME, Phamduy TB, Sharpe AH and Freeman GJ: Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 27:111–122. 2007. View Article : Google Scholar : PubMed/NCBI
20	Ghiotto M, Gauthier L, Serriari N, Pastor S, Truneh A, Nunès JA and Olive D: PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1. Int Immunol. 22:651–660. 2010. View Article : Google Scholar : PubMed/NCBI
21	Zheng P and Zhou Z: Human cancer immunotherapy with PD-1/PD-L1 blockade. Biomark Cancer. 7 (Suppl 2):S15–S18. 2015.
22	Catakovic K, Klieser E, Neureiter D and Geisberger R: T cell exhaustion: From pathophysiological basics to tumor immunotherapy. Cell Commun Signal. 15:12017. View Article : Google Scholar : PubMed/NCBI
23	Patel SP and Kurzrock R: PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 14:847–856. 2015. View Article : Google Scholar : PubMed/NCBI
24	Palaga T, Miele L, Golde TE and Osborne BA: TCR-mediated Notch signaling regulates proliferation and IFN-gamma production in peripheral T cells. J Immunol. 171:3019–3024. 2003. View Article : Google Scholar : PubMed/NCBI
25	Iwasaki M, Tanaka Y, Kobayashi H, Murata-Hirai K, Miyabe H, Sugie T, Toi M and Minato N: Expression and function of PD-1 in human γδ T cells that recognize phosphoantigens. Eur J Immunol. 41:345–355. 2011. View Article : Google Scholar : PubMed/NCBI
26	Wang D, Lin J, Yang X, Long J, Bai Y, Yang X, Mao Y, Sang X, Seery S and Zhao H: Combination regimens with PD-1/PD-L1 immune checkpoint inhibitors for gastrointestinal malignancies. J Hematol Oncol. 12:422019. View Article : Google Scholar : PubMed/NCBI
27	Macian F: NFAT proteins: Key regulators of T-cell development and function. Nat Rev Immunol. 5:472–484. 2005. View Article : Google Scholar : PubMed/NCBI
28	Grievink HW, Luisman T, Kluft C, Moerland M and Malone KE: Comparison of three isolation techniques for human peripheral blood mononuclear cells: Cell recovery and viability, population composition, and cell functionality. Biopreserv Biobank. 14:410–415. 2016. View Article : Google Scholar : PubMed/NCBI
29	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
30	Patsoukis N, Brown J, Petkova V, Liu F, Li L and Boussiotis VA: Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal. 5:ra462012. View Article : Google Scholar : PubMed/NCBI
31	Vaeth M and Feske S: NFAT control of immune function: New frontiers for an abiding trooper. F1000Res. 7:2602018. View Article : Google Scholar : PubMed/NCBI
32	Ponomarev V, Doubrovin M, Lyddane C, Beresten T, Balatoni J, Bornman W, Finn R, Akhurst T, Larson S, Blasberg R, et al: Imaging TCR-dependent NFAT-mediated T-cell activation with positron emission tomography in vivo. Neoplasia. 3:480–488. 2001. View Article : Google Scholar : PubMed/NCBI
33	Ding ZC, Lu XY, Yu M, Lemos H, Huang L, Chandler P, Liu K, Walters M, Krasinski A, Mack M, et al: Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-Cell Responses through the PD-1-PD-L1 Axis. Cancer Res. 74:3441–3453. 2014. View Article : Google Scholar : PubMed/NCBI
34	Medina PJ and Adams VR: PD-1 Pathway Inhibitors: Immuno-oncology agents for restoring antitumor immune responses. Pharmacotherapy. 36:317–334. 2016. View Article : Google Scholar : PubMed/NCBI
35	Liu Y and Cao XT: Immunosuppressive cells in tumor immune escape and metastasis. J Mol Med. 94:509–522. 2016. View Article : Google Scholar : PubMed/NCBI
36	Dustin ML: The cellular context of T cell signaling. Immunity. 30:482–492. 2009. View Article : Google Scholar : PubMed/NCBI
37	Zhu X, Kim JL, Newcomb JR, Rose PE, Stover DR, Toledo LM, Zhao H and Morgenstern KA: Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors. Structure. 7:651–661. 1999. View Article : Google Scholar : PubMed/NCBI
38	Li M, Ong SS, Rajwa B, Thieu VT, Geahlen RL and Harrison ML: The SH3 domain of Lck modulates T-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of Raf-1. Mol Cell Biol. 28:630–641. 2008. View Article : Google Scholar : PubMed/NCBI
39	Beyersdorf N, Kerkau T and Hunig T: CD28 co-stimulation in T-cell homeostasis: A recent perspective. Immunotargets Ther. 4:111–122. 2015.PubMed/NCBI
40	Parry RV, Riley JL and Ward SG: Signalling to suit function: Tailoring phosphoinositide 3-kinase during T-cell activation. Trends Immunol. 28:161–168. 2007. View Article : Google Scholar : PubMed/NCBI
41	Butler DE, Marlein C, Walker HF, Frame FM, Mann VM, Simms MS, Davies BR, Collins AT and Maitland NJ: Inhibition of the PI3K/AKT/mTOR pathway activates autophagy and compensatory Ras/Raf/MEK/ERK signalling in prostate cancer. Oncotarget. 8:56698–56713. 2017. View Article : Google Scholar : PubMed/NCBI
42	Asati V, Mahapatra DK and Bharti SK: PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur J Med Chem. 109:314–341. 2016. View Article : Google Scholar : PubMed/NCBI
43	Mahoney KM, Freeman GJ and McDermott DF: The next immune-checkpoint inhibitors: PD-1/PD-L1 blockade in melanoma. Clin Ther. 37:764–782. 2015. View Article : Google Scholar : PubMed/NCBI
44	Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, Sasmal DK, Huang J, Kim JM, Mellman I and Vale RD: T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 355:1428–1433. 2017. View Article : Google Scholar : PubMed/NCBI
45	Jacquin-Porretaz C, Nardin C, Puzenat E, Roche-Kubler B and Aubin F; Comité de suivi des effets secondaires des immunothérapies anti-cancéreuses (CSESIAC), : Adverse effects of immune checkpoint inhibitors used to treat melanoma and other cancer. Presse Med. 46:808–817. 2017.(In French). View Article : Google Scholar : PubMed/NCBI
46	Park JA and Cheung NV: Erratum to ‘limitations and opportunities for immune checkpoint inhibitors in pediatric malignancies’ [Cancer Treat. Rev. 58C (2017) 22–33]. Cancer Treat Rev. 60:1582017. View Article : Google Scholar : PubMed/NCBI
47	McDermott DF and Atkins MB: PD-1 as a potential target in cancer therapy. Cancer Med. 2:662–673. 2013.PubMed/NCBI