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Molecular Diagnostics

IL-33/ST2 signaling promotes constitutive and inductive PD-L1 expression and immune escape in oral squamous cell carcinoma

British Journal of Cancer volume 128, pages 833–843 (2023)Cite this article

Subjects

Abstract

Background

Loss-of-function of PD-L1 induces therapy resistance of anti-PD-1/L1 therapy, and the complex regulatory mechanisms are not completely understood. We previously reported that stroma-derived interleukin-33 (IL-33) promoted the progression of oral squamous cell carcinoma (OSCC). We here focused on the immune-regulation role of IL-33 and its receptor ST2 signaling in PD-L1-positive OSCC patients.

Methods

Activated T cells in in situ and peripheral blood were analyzed by IL-33/ST3 expression. Knockdown or overexpression of ST2 combined with IL-33/IFN-γ stimulation were performed to determine PD-L1 expression and PD-L1-dependent immune escape in OSCC/human T cells co-culture system, and OSCC orthotopic model based on humanized mouse with immune reconstitution and C57BL/6 mice models.

Results

High IL-33/ST2 correlated with less activated T cells infiltration in situ and peripheral blood. Knockdown of ST2 down-regulated constitutive PD-L1 expression, whereas ST2 also promoted IL-33-induced PD-L1 Mechanistically, IL-33/ST2 activated JAK2/STAT3 pathway to directly promoted PD-L1 expression, and also activated MyD88/NF-κB signaling to up-regulate IFN-γ receptor (IFN-γR), which indirectly strengthen IFN-γ-induced PD-L1. Furthermore, ST2 is required for PD-L1-mediated immune tolerance in vitro and in vivo. ST2high OSCC patients have more PD-L1 and IFN-γR level in situ.

Conclusions

IL-33/ST2 signaling enhanced PD-L1-mediated immune escape, ST2high OSCC patients might benefit from anti-PD-1/L1 therapy.

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Fig. 1: Correlations between IL-33/ST2 and T cells activation in situ and blood.
Fig. 2: IL-33/ST2 signal in OSCC regulates the expression of PD-L1.
Fig. 3: The role of JAK2/STAT3 pathway in the regulation of PD-L1 expression by IL-33/ST2.
Fig. 4: The impacts of IL-33/ST2 signaling on IFN-γR/PD-L1 expression of tumor cells.
Fig. 5: ST2 knockdown promote the human CTL killing function in vitro and in vivo of Hu-PBMC mouse model.
Fig. 6: ST2 knockdown combines with anti-PD-L1 therapy show superior anti-tumor effects in OSCC.

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Data availability

All of the data generated or analyzed in this study are included in this published article.

References

  1. Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394:1915–28.

    Article  CAS  PubMed  Google Scholar 

  2. Cramer JD, Burtness B, Ferris RL. Immunotherapy for head and neck cancer: Recent advances and future directions. Oral Oncol. 2019;99:104460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ribas A, Hu-Lieskovan S. What does PD-L1 positive or negative mean? J Exp Med. 2016;213:2835–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Shen X, Zhao B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ. 2018;362:k3529.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Pires da Silva I, Ahmed T, Reijers ILM, Weppler AM, Betof Warner A, Patrinely JR, et al. Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study. Lancet Oncol. 2021;22:836–47.

    Article  CAS  PubMed  Google Scholar 

  6. Yi M, Jiao D, Xu H, Liu Q, Zhao W, Han X, et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer. 2018;17:129.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Saigi M, Alburquerque-Bejar JJ, Mc Leer-Florin A, Pereira C, Pros E, Romero OA, et al. MET-oncogenic and JAK2-inactivating alterations are independent factors that affect regulation of PD-L1 expression in lung cancer. Clin Cancer Res. 2018;24:4579–87.

    Article  CAS  PubMed  Google Scholar 

  8. Barroso-Sousa R, Keenan TE, Pernas S, Exman P, Jain E, Garrido-Castro AC, et al. Tumor mutational burden and PTEn alterations as molecular correlates of response to PD-1/L1 blockade in metastatic triple-negative breast cancer. Clin Cancer Res. 2020;26:2565–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yu M, Peng Z, Qin M, Liu Y, Wang J, Zhang C, et al. Interferon-gamma induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation. Mol Cell. 2021;81:1216–30.e1219.

    Article  CAS  PubMed  Google Scholar 

  10. Wu T, Dai Y. Tumor microenvironment and therapeutic response. Cancer Lett. 2017;387:61–68.

    Article  CAS  PubMed  Google Scholar 

  11. Feng J, Yang H, Zhang Y, Wei H, Zhu Z, Zhu B, et al. Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene. 2017;36:5829–39.

    Article  CAS  PubMed  Google Scholar 

  12. Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017;545:495–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211:781–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA. 2013;110:20212–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ding L, Ren J, Zhang D, Li Y, Huang X, Hu Q, et al. A novel stromal lncRNA signature reprograms fibroblasts to promote the growth of oral squamous cell carcinoma via LncRNA-CAF/interleukin-33. Carcinogenesis. 2018;39:397–406.

    Article  CAS  PubMed  Google Scholar 

  16. Zhao X, Ding L, Lu Z, Huang X, Jing Y, Yang Y, et al. Diminished CD68(+) cancer-associated fibroblast subset induces regulatory T-cell (Treg) infiltration and predicts poor prognosis of oral squamous cell carcinoma patients. Am J Pathol. 2020;190:886–99.

    Article  CAS  PubMed  Google Scholar 

  17. Wang Y, Jing Y, Ding L, Zhang X, Song Y, Chen S, et al. Epiregulin reprograms cancer-associated fibroblasts and facilitates oral squamous cell carcinoma invasion via JAK2-STAT3 pathway. J Exp Clin cancer Res: CR. 2019;38:274.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ding L, Ren J, Zhang D, Li Y, Huang X, Ji J, et al. The TLR3 agonist inhibit drug efflux and sequentially consolidates low-dose cisplatin-based chemoimmunotherapy while reducing side effects. Mol Cancer Ther. 2017;16:1068–79.

    Article  CAS  PubMed  Google Scholar 

  19. Cayrol C, Girard JP. Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. Immunol Rev. 2018;281:154–68.

    Article  CAS  PubMed  Google Scholar 

  20. Son J, Cho JW, Park HJ, Moon J, Park S, Lee H, et al. Tumor-infiltrating regulatory T-cell accumulation in the tumor microenvironment is mediated by IL33/ST2 signaling. Cancer Immunol Res. 2020;8:1393–406.

    Article  CAS  PubMed  Google Scholar 

  21. Wen YH, Lin HQ, Li H, Zhao Y, Lui VWY, Chen L, et al. Stromal interleukin-33 promotes regulatory T cell-mediated immunosuppression in head and neck squamous cell carcinoma and correlates with poor prognosis. Cancer Immunol Immunother. 2019;68:221–32.

    Article  CAS  PubMed  Google Scholar 

  22. Ding Z, He Y, Fu Y, Zhu N, Zhao M, Song Y, et al. CD38 multi-functionality in oral squamous cell carcinoma: prognostic implications, immune balance, and immune checkpoint. Front Oncol. 2021;11:687430.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127:2930–40.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Griesenauer B, Jiang H, Yang J, Zhang J, Ramadan AM, Egbosiuba J, et al. ST2/MyD88 deficiency protects mice against acute graft-versus-host disease and spares regulatory T cells. J Immunol. 2019;202:3053–64.

    Article  CAS  PubMed  Google Scholar 

  25. Griesenauer B, Paczesny S. The ST2/IL-33 axis in immune cells during inflammatory diseases. Front Immunol. 2017;8:475.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wang L, Luo Y, Luo L, Wu D, Ding X, Zheng H, et al. Adiponectin restrains ILC2 activation by AMPK-mediated feedback inhibition of IL-33 signaling. J Exp Med. 2021;218:e20191054.

    Article  CAS  PubMed  Google Scholar 

  27. Shirey KA, Jung JY, Maeder GS, Carlin JM. Upregulation of IFN-gamma receptor expression by proinflammatory cytokines influences IDO activation in epithelial cells. J Interferon Cytokine Res. 2006;26:53–62.

    Article  CAS  PubMed  Google Scholar 

  28. Liu S, Knochelmann HM, Lomeli SH, Hong A, Richardson M, Yang Z, et al. Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma. Cell Rep. Med. 2021;2:100411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dominguez CX, Muller S, Keerthivasan S, Koeppen H, Hung J, Gierke S, et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15(+) myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Disco. 2020;10:232–53.

    Article  CAS  Google Scholar 

  30. Galbo PM Jr, Zang X, Zheng D. Molecular features of cancer-associated fibroblast subtypes and their implication on cancer pathogenesis, prognosis, and immunotherapy resistance. Clin Cancer Res. 2021;27:2636–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Inoue C, Miki Y, Saito R, Hata S, Abe J, Sato I, et al. PD-L1 induction by cancer-associated fibroblast-derived factors in lung adenocarcinoma cells. Cancers (Basel). 2019;11:1257.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang M, Shi R, Guo Z, He J. Cancer-associated fibroblasts promote cell growth by activating ERK5/PD-L1 signaling axis in colorectal cancer. Pathol Res Pract. 2020;216:152884.

    Article  CAS  PubMed  Google Scholar 

  33. Lin Y, Cai Q, Chen Y, Shi T, Liu W, Mao L, et al. CAFs shape myeloid-derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma through 5-lipoxygenase. Hepatology. 2022;75:28–42.

    Article  CAS  PubMed  Google Scholar 

  34. Peng S, Wang R, Zhang X, Ma Y, Zhong L, Li K, et al. EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression. Mol Cancer. 2019;18:165.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Guo Y, Song J, Wang Y, Huang L, Sun L, Zhao J, et al. Concurrent genetic alterations and other biomarkers predict treatment efficacy of EGFR-TKIs in EGFR-mutant non-small cell lung cancer: a review. Front Oncol. 2020;10:610923.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Clark JT, Christian DA, Gullicksrud JA, Perry JA, Park J, Jacquet M, et al. IL-33 promotes innate lymphoid cell-dependent IFN-gamma production required for innate immunity to Toxoplasma gondii. Elife 2021;10:e65614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hatzioannou A, Banos A, Sakelaropoulos T, Fedonidis C, Vidali MS, Kohne M, et al. An intrinsic role of IL-33 in Treg cell-mediated tumor immunoevasion. Nat Immunol. 2020;21:75–85.

    Article  CAS  PubMed  Google Scholar 

  38. Park SH, Kim MS, Lim HX, Cho D, Kim TS. IL-33-matured dendritic cells promote Th17 cell responses via IL-1beta and IL-6. Cytokine. 2017;99:106–13.

    Article  CAS  PubMed  Google Scholar 

  39. Ganesan S, Pham D, Jing Y, Farazuddin M, Hudy MH, Unger B, et al. TLR2 activation limits rhinovirus-stimulated CXCL-10 by attenuating IRAK-1-dependent IL-33 receptor signaling in human Bronchial epithelial cells. J Immunol. 2016;197:2409–20.

    Article  CAS  PubMed  Google Scholar 

  40. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479–90.

    Article  CAS  PubMed  Google Scholar 

  41. Choi YS, Choi HJ, Min JK, Pyun BJ, Maeng YS, Park H, et al. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood. 2009;114:3117–26.

    Article  CAS  PubMed  Google Scholar 

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Funding

Research was supported by grants by the National Natural Science Foundation of China (Grant No. 81902754, 82002865); Natural Science Foundation of Jiangsu Province (No. BK20190304, BE2020628); Nanjing Medical Science and Technology Development Foundation, Nanjing Department of Health (No. YKK21182, YKK20151).

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Author notes

  1. These authors contributed equally: Mengxiang Zhao, Yijia He, Nisha Zhu.

Authors and Affiliations

  1. Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, 22 Hankou Road, Nanjing, 210093, China

    Mengxiang Zhao, Yijia He, Nisha Zhu, Yuxian Song, Qingang Hu, Yanhong Ni & Liang Ding

  2. Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China

    Mengxiang Zhao & Zhiyong Wang

  3. Department of Stomatology, Ningbo First Hospital, 59 Liuting street, Ningbo, 315000, China

    Mengxiang Zhao

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Contributions

Conceptualization: LD, YHN and ZYW; data curation: MXZ; formal analysis: MXZ and YXS; methodology: LD, NSZ and YJH, and MXZ; investigation: NSZ, and MXZ; supervision: LD, YHN, and QGH; validation: YHN; Writing—original draft: LD and MXZ.

Corresponding authors

Correspondence to Zhiyong Wang, Yanhong Ni or Liang Ding.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Ethical approval for this study including tumor biopsy and serum collection was obtained from the Research Ethics Committee of Nanjing Stomatology Hospital (No.2019NL-009(KS)) and informed consent was obtained from the patients. The study was performed in accordance with the Declaration of Helsinki. All animal experiments were performed in accordance with Jiangsu Association for Laboratory Animal Science (Authorization Number: 220195073) and were subject to review by the animal welfare and ethical review board of Nanjing university.

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Zhao, M., He, Y., Zhu, N. et al. IL-33/ST2 signaling promotes constitutive and inductive PD-L1 expression and immune escape in oral squamous cell carcinoma. Br J Cancer 128, 833–843 (2023). https://doi.org/10.1038/s41416-022-02090-0

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