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Increased coexpression of PD-L1 and IDO1 is associated with poor overall survival in patients with NK/T-cell lymphoma

Leukemia volume 38, pages 1553–1563 (2024)Cite this article

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Abstract

Immunotherapy with programmed cell death 1 ligand 1 (PD-L1) blockade was effective in patients with NK/T-cell lymphoma. In addition to PD-L1, indoleamine 2,3-dioxygenase-1 (IDO1) is one of the most promising immunotherapeutic targets. High proportions of PD-L1 and IDO1 proteins were observed by immunohistochemistry (IHC) from 230 newly diagnosed patients with NK/T lymphoma with tissue samples from three cancer centers and were associated with poor overall survival (OS) in patients with NK/T lymphoma. Importantly, the coexpression of PD-L1 and IDO1 was related to poor OS and short restricted mean survival time in patients with NK/T lymphoma and was an independent prognostic factor in the training cohorts, and which was also validated in 58 NK/T lymphoma patients (GSE90597). Moreover, a nomogram model constructed with PD-L1 and IDO1 expression together with age could provide concise and precise predictions of OS rates and median survival time. The high-risk group in the nomogram model had a positive correlation with CD4 + T-cell infiltration in the validation cohort, as did the immunosuppressive factor level. Therefore, high PD-L1 and IDO1 expression was associated with poor OS in patients with NK/T lymphoma. PD-L1 and IDO1 might be potential targets for future immune checkpoint blockade (ICB) therapy for NK/T lymphoma.

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Fig. 1: Workflow chart of the data enrollment and analysis for developing a prognostic model with PD-L1 and IDO1.
Fig. 2: Increased PD-L1 or IDO1 expression predicted poor OS in patients with NK/T-cell lymphoma.
Fig. 3: Coexpression of PD-L1 and IDO1 predicted poor OS in patients with NK/T-cell lymphoma.
Fig. 4: Establishment of the nomogram model.
Fig. 5: Immune-related characteristics of NK/T-cell lymphoma patients in the validation cohort based on the nomogram model.

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Data availability

Data used in this work can be acquired from the Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792272/bin/supp_2017.180430_haematol.2017.180430.DC1.html).

References

  1. Anderson JR, Armitage JO, Weisenburger DD. Epidemiology of the non-Hodgkin’s lymphomas: distributions of the major subtypes differ by geographic locations. Non-Hodgkin’s lymphoma classification project. Ann Oncol. 1998;9:717–20.

    CAS  PubMed  Google Scholar 

  2. Yang Y, Wang Y, Liu X, He X, Zhang LL, Wu G, et al. Progression-free survival at 24 months and subsequent survival of patients with extranodal NK/T-cell lymphoma: a China Lymphoma Collaborative Group (CLCG) study. Leukemia. 2021;35:1671–82.

    CAS  PubMed  Google Scholar 

  3. Kim TM, Lee SY, Jeon YK, Ryoo BY, Cho GJ, Hong YS, et al. Clinical heterogeneity of extranodal NK/T-cell lymphoma, nasal type: a national survey of the Korean Cancer Study Group. Ann Oncol. 2008;19:1477–84.

    CAS  PubMed  Google Scholar 

  4. Yoon SE, Song Y, Kim SJ, Yoon DH, Chen TY, Koh Y, et al. Comprehensive analysis of peripheral T-cell and natural killer/T-cell lymphoma in Asian patients: a multinational, multicenter, prospective registry study in Asia. Lancet Reg Health Western Pac. 2021;10:100126.

    Google Scholar 

  5. Wang H, Fu BB, Gale RP, Liang Y. NK-/T-cell lymphomas. Leukemia. 2021;35:2460–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Tse E, Zhao WL, Xiong J, Kwong YL. How we treat NK/T-cell lymphomas. J Hematol Oncol. 2022;15:74.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–84.

    CAS  PubMed  Google Scholar 

  8. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol. 2016;34:2698–704.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim SJ, Lim JQ, Laurensia Y, Cho J, Yoon SE, Lee JY, et al. Avelumab for the treatment of relapsed or refractory extranodal NK/T-cell lymphoma: an open-label phase 2 study. Blood. 2020;136:2754–63.

    CAS  PubMed  Google Scholar 

  11. Kwong YL, Chan TSY, Tan D, Kim SJ, Poon LM, Mow B, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood. 2017;129:2437–42.

    CAS  PubMed  Google Scholar 

  12. Zhai L, Ladomersky E, Lenzen A, Nguyen B, Patel R, Lauing KL, et al. IDO1 in cancer: a Gemini of immune checkpoints. Cell Molecul Immunol. 2018;15:447–57.

    CAS  Google Scholar 

  13. Matutes E. The 2017 WHO update on mature T- and natural killer (NK) cell neoplasms. Int J Lab Hematol. 2018;40:97–103.

    PubMed  Google Scholar 

  14. Theate I, van Baren N, Pilotte L, Moulin P, Larrieu P, Renauld JC, et al. Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues. Cancer Immunol Res. 2015;3:161–72.

    CAS  PubMed  Google Scholar 

  15. Ino K, Yoshida N, Kajiyama H, Shibata K, Yamamoto E, Kidokoro K, et al. Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer. Br J Cancer. 2006;95:1555–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Klepsch V, Hermann-Kleiter N, Do-Dinh P, Jakic B, Offermann A, Efremova M, et al. Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade. Nature Commun. 2018;9:1538.

    Google Scholar 

  17. Chen K, Gong S, Fang X, Li Q, Ye M, Li J, et al. Non-coding RNA-mediated high expression of SFXN3 as a prognostic biomarker associated with paclitaxel resistance and immunosuppressive microenvironment in head and neck cancer. Front Immunol. 2022;13:920136.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Li X, Cheng Y, Zhang M, Yan J, Li L, Fu X, et al. Activity of pembrolizumab in relapsed/refractory NK/T-cell lymphoma. J Hematol Oncol. 2018;11:15.

    PubMed  PubMed Central  Google Scholar 

  19. Lim JQ, Huang D, Tang T, Tan D, Laurensia Y, Peng RJ, et al. Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma. Leukemia. 2020;34:3413–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Tao R, Fan L, Song Y, Hu Y, Zhang W, Wang Y, et al. Sintilimab for relapsed/refractory extranodal NK/T cell lymphoma: a multicenter, single-arm, phase 2 trial (ORIENT-4). Signal Transduct Target Ther. 2021;6:365.

    PubMed  PubMed Central  Google Scholar 

  21. Huang H, Tao R, Hao S, Yang Y, Cen H, Zhou H, et al. Sugemalimab monotherapy for patients with relapsed or refractory extranodal natural Killer/T-cell lymphoma (GEMSTONE-201): results from a single-arm, multicenter, phase II study. J Clin Oncol. 2023;41:3032–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Cai J, Liu P, Huang H, Li Y, Ma S, Zhou H, et al. Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma. Signal Transduct Target Ther. 2020;5:289.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. de Charette M, Houot R. Hide or defend, the two strategies of lymphoma immune evasion: potential implications for immunotherapy. Haematologica. 2018;103:1256–68.

    PubMed  PubMed Central  Google Scholar 

  24. Boon T, van der Bruggen P. Human tumor antigens recognized by T lymphocytes. J Exp Med. 1996;183:725–9.

    CAS  PubMed  Google Scholar 

  25. Kline J, Godfrey J, Ansell SM. The immune landscape and response to immune checkpoint blockade therapy in lymphoma. Blood. 2020;135:523–33.

    CAS  PubMed  Google Scholar 

  26. Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 2019;18:10.

    PubMed  PubMed Central  Google Scholar 

  27. Li JW, Wei P, Guo Y, Shi D, Yu BH, Su YF, et al. Clinical significance of circulating exosomal PD-L1 and soluble PD-L1 in extranodal NK/T-cell lymphoma, nasal-type. Am J Cancer Res. 2020;10:4498–512.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang XW, Bi XW, Liu PP, Liu ZL, Nie M, Yang H, et al. Expression of PD-L1 on Monocytes Is A Novel Predictor Of Prognosis In Natural Killer/t-cell Lymphoma. Front Oncol. 2020;10:1360.

    PubMed  PubMed Central  Google Scholar 

  29. Zahm CD, Johnson LE, McNeel DG. Increased indoleamine 2,3-dioxygenase activity and expression in prostate cancer following targeted immunotherapy. Cancer Immunol Immunother. 2019;68:1661–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Choe JY, Yun JY, Jeon YK, Kim SH, Park G, Huh JR, et al. Indoleamine 2,3-dioxygenase (IDO) is frequently expressed in stromal cells of Hodgkin lymphoma and is associated with adverse clinical features: a retrospective cohort study. BMC Cancer. 2014;14:335.

    PubMed  PubMed Central  Google Scholar 

  31. Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today. 1999;20:469–73.

    CAS  PubMed  Google Scholar 

  32. Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9:1269–74.

    CAS  PubMed  Google Scholar 

  33. Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002;196:459–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ninomiya S, Hara T, Tsurumi H, Hoshi M, Kanemura N, Goto N, et al. Indoleamine 2,3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP. Ann Hematol. 2011;90:409–16.

    CAS  PubMed  Google Scholar 

  35. Masaki A, Ishida T, Maeda Y, Ito A, Suzuki S, Narita T, et al. Clinical significance of tryptophan catabolism in Hodgkin lymphoma. Cancer Sci. 2018;109:74–83.

    CAS  PubMed  Google Scholar 

  36. Sugio T, Miyawaki K, Kato K, Sasaki K, Yamada K, Iqbal J, et al. Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS. Blood Adv. 2018;2:2242–52.

    PubMed  PubMed Central  Google Scholar 

  37. Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med. 2013;210:1389–402.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kocher F, Amann A, Zimmer K, Geisler S, Fuchs D, Pichler R, et al. High indoleamine-2,3-dioxygenase 1 (IDO) activity is linked to primary resistance to immunotherapy in non-small cell lung cancer (NSCLC). Transl Lung Cancer Res. 2021;10:304–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Brown ZJ, Yu SJ, Heinrich B, Ma C, Fu Q, Sandhu M, et al. Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma. Cancer Immunol Immunother. 2018;67:1305–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Nam SJ, Kim S, Kwon D, Kim H, Kim S, Lee E, et al. Prognostic implications of tumor-infiltrating macrophages, M2 macrophages, regulatory T-cells, and indoleamine 2,3-dioxygenase-positive cells in primary diffuse large B-cell lymphoma of the central nervous system. Oncoimmunology. 2018;7:e1442164.

    PubMed  PubMed Central  Google Scholar 

  41. Chen C, Liang C, Wang S, Chio CL, Zhang Y, Zeng C, et al. Expression patterns of immune checkpoints in acute myeloid leukemia. J Hematol Oncol. 2020;13:28.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang P, Chen Y, Long Q, Li Q, Tian J, Liu T, et al. Increased coexpression of PD-L1 and TIM3/TIGIT is associated with poor overall survival of patients with esophageal squamous cell carcinoma. J Immunother Cancer. 2021;9:e002836.

    PubMed  PubMed Central  Google Scholar 

  43. Beatty GL, O’Dwyer PJ, Clark J, Shi JG, Bowman KJ, Scherle PA, et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin Cancer Res. 2017;23:3269–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Gangadhar TC, Schneider BJ, Bauer TM, Wasser JS, Spira AI, Patel SP, et al. Efficacy and safety of epacadostat plus pembrolizumab treatment of NSCLC: preliminary phase I/II results of ECHO-202/KEYNOTE-037. J Clin Oncol. 2017;35:9014–9014. 2017/05/20

    Google Scholar 

  45. Bi XW, Wang H, Zhang WW, Wang JH, Liu WJ, Xia ZJ, et al. PD-L1 is upregulated by EBV-driven LMP1 through NF-kappaB pathway and correlates with poor prognosis in natural killer/T-cell lymphoma. J Hematol Oncol. 2016;9:109.

    PubMed  PubMed Central  Google Scholar 

  46. Zeng L, Huang W, Cao Z, Zheng B, Liu X, Guo L, et al. The correlation of clinicopathological features and prognosis in extranodal natural killer/T cell lymphoma: a report of 42 cases in the early stage. Ann Hematol. 2019;98:1467–76.

    CAS  PubMed  Google Scholar 

  47. Muhamad H, Suksawai N, Assanasen T, Polprasert C, Bunworasate U, Wudhikarn K. Programmed cell death 1 and programmed cell death ligands in extranodal natural killer/t cell lymphoma: expression pattern and potential prognostic relevance. Acta Haematol. 2020;143:78–88.

    CAS  PubMed  Google Scholar 

  48. Lam ST, Huang H, Fang X, Wang Z, Hong H, Ren Q, et al. A new immunological prognostic model based on immunohistochemistry for extranodal natural killer/t-cell lymphoma patients after non-anthracycline-based chemotherapy. Cancer Manag Res. 2020;12:1981–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kim WY, Jung HY, Nam SJ, Kim TM, Heo DS, Kim CW, et al. Expression of programmed cell death ligand 1 (PD-L1) in advanced stage EBV-associated extranodal NK/T cell lymphoma is associated with better prognosis. Virchows Arch. 2016;469:581–90.

    CAS  PubMed  Google Scholar 

  50. Gao LM, Zhang YH, Shi X, Liu Y, Wang J, Zhang WY, et al. The Role of PD-L1 Expression in Prediction and Stratification of Recurrent or Refractory Extranodal Natural Killer/T-Cell Lymphoma. Front Oncol. 2022;12:821918.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Jo JC, Kim M, Choi Y, Kim HJ, Kim JE, Chae SW, et al. Expression of programmed cell death 1 and programmed cell death ligand 1 in extranodal NK/T-cell lymphoma, nasal type. Ann Hematol. 2017;96:25–31.

    CAS  PubMed  Google Scholar 

  52. Zhou QH, Li KW, Chen X, He HX, Peng SM, Peng SR, et al. HHLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma. J Immunother Cancer. 2020;8:e000157.

    PubMed  PubMed Central  Google Scholar 

  53. Takada K, Kohashi K, Shimokawa M, Haro A, Osoegawa A, Tagawa T, et al. Co-expression of IDO1 and PD-L1 in lung squamous cell carcinoma: Potential targets of novel combination therapy. Lung Cancer. 2019;128:26–32.

    PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Sailing Program of Hunan Cancer Hospital (No. QH201902); Hunan Provincial Natural Science Foundation of China (No. 2021JJ30425); Hunan Provincial Natural Science Foundation of China (No. 2022JJ30026); the Changsha Municipal Natural Science Foundation (No. kq2014206); the Natural Science Foundation of Hunan Province National Health Commission (No. 20201659); the “Scientific Research Climbing Plan” of Hunan Cancer Hospital (grant number ZX2020003).

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  1. These authors contributed equally: Yajun Li, Kailin Chen, Bihua Chen.

Authors and Affiliations

  1. Department of Lymphoma and Hematology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, 410013, China

    Yajun Li, Bihua Chen, Ruolan Zeng, Yizi He, Caiqin Wang & Hui Zhou

  2. Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, 410013, China

    Kailin Chen

  3. Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China

    Meizuo Zhong

  4. Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410013, China

    Xianling Liu

  5. Department of Pathology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, 410013, China

    Xiaoyan Chen

  6. Department of Histology and Embryology of School of Basic Medical Science, Central South University, Changsha, Hunan, 410013, China

    Ling Xiao

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Contributions

YL: Designed the signature, analyzed the data, prepared the figures, revised the manuscript. KC: Analyzed the data, prepared the figures, interpreted the results, supervised the analyses, drafted the manuscript. BC: Collected the data, interpreted the results, revised the manuscript. RZ: Acquired the data, interpreted the results, revised the manuscript. YH: Acquired the data, interpreted the results, revised the manuscript. CW: Acquired the data, interpreted the results, revised the manuscript. MZ: Collected the data, revised the manuscript. XL: Collected the data, revised the manuscript. XC: Evaluate and scored slides, revised the manuscript. LX: Conceived and supervised the work, revised the manuscript. HZ: Conceived and supervised the work, drafted the manuscript. All the authors approved the final version.

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Correspondence to Ling Xiao or Hui Zhou.

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Li, Y., Chen, K., Chen, B. et al. Increased coexpression of PD-L1 and IDO1 is associated with poor overall survival in patients with NK/T-cell lymphoma. Leukemia 38, 1553–1563 (2024). https://doi.org/10.1038/s41375-024-02266-y

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