Skip to main content

Advertisement

SpringerLink
Log in

Novel tumour–infiltrating lymphocyte-related risk stratification based by flow cytometry for patients with de novo angioimmunoblastic T cell lymphoma

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Tumour-infiltrating lymphocytes (TILs) account for a large proportion of tumour microenvironment (TME) in angioimmunoblastic T cell lymphoma (AITL), and at present the significance of TIL in TME of AITL remains unclear. Overall, 50 de novo AITL patients undergoing lymph node flow cytometry from 2014 to 2019 were retrospectively analysed to assess the relationship between TILs and AITL prognosis. We found that high TIL-Bs (≥ 42.4%, p = 0.004) and high CD4:CD8 (≥ 0.85, p = 0.024) were independent favourable prognostic factors for de novo AITL in univariate or multivariate analyses. New TIL-related risk stratification was established based on TIL-Bs and CD4:CD8 factors. Patients in the low-risk group (TIL-Bs ≥ 42.4% and CD4:CD8 ≥ 0.85) had significantly better overall survival than the high-risk (TIL-Bs < 42.4% and CD4:CD8 < 0.85) (p < 0.001) or intermediate-risk group (TIL-Bs ≥ 42.4% and CD4:CD8 < 0.85 or TIL-Bs < 42.4% and CD4:CD8 ≥ 0.85) (p = 0.011). To our knowledge, our cohort is the largest one focusing on the TILs in de novo cases of AITL by analysing lymph node samples using flow cytometry, which is the first time to comprehensively consider humoral immunity and cellular immunity influence on AITL. Our new risk stratification was valuable and useful in evaluating prognosis of AITL and guiding immunotherapy strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Chiba S, Sakata-Yanagimoto M (2020) Advances in understanding of angioimmunoblastic T-cell lymphoma. Leukemia 34(10):2592–2606

    Article  PubMed  PubMed Central  Google Scholar 

  2. Lemonnier F, Mak TW (2017) Angioimmunoblastic T-cell lymphoma: more than a disease of T follicular helper cells. J Pathol 242(4):387–390

    Article  CAS  PubMed  Google Scholar 

  3. Mourad N, Mounier N, Brière J, Raffoux E, Delmer A, Feller A, Meijer CJ, Emile JF, Bouabdallah R, Bosly A, Diebold J, Haioun C, Coiffier B, Gisselbrecht C, Gaulard P (2008) Clinical, biologic, and pathologic features in 157 patients with angioimmunoblastic T-cell lymphoma treated within the Groupe d’Etude des Lymphomes de l’Adulte (GELA) trials. Blood 111(9):4463–4470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lunning MA, Vose JM (2017) Angioimmunoblastic T-cell lymphoma: the many-faced lymphoma. Blood 129(9):1095–1102

    Article  CAS  PubMed  Google Scholar 

  5. De Leval L, Gisselbrecht C, Gaulard P (2010) Advances in the understanding and management of angioimmunoblastic T-cell lymphoma. Br J Haematol 148(5):673–689

    Article  PubMed  CAS  Google Scholar 

  6. Merchant SH, Amin MB, Viswanatha DS (2006) Morphologic and immunophenotypic analysis of angioimmunoblastic T-cell lymphoma: emphasis on phenotypic aberrancies for early diagnosis. Am J Clin Pathol 126(1):29–38

    Article  PubMed  Google Scholar 

  7. De Leval L, Rickman DS, Thielen C, Reynies A, Huang YL, Delsol G, Lamant L, Leroy K, Briere J, Molina T, Berger F, Gisselbrecht C, Xerri L, Gaulard P (2007) The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood 109(11):4952–4963

    Article  PubMed  CAS  Google Scholar 

  8. Bruneau J, Canioni D, Renand A, Marafioti T, Paterson JC, Martin-Garcia N, Gaulard P, Delfau MH, Hermine O, Macintyre E (2010) Regulatory T-cell depletion in angioimmunoblastic T-cell lymphoma. Am J Pathol 177(2):570–574

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chen Z, Deng X, Ye Y, Gao L, Zhang W, Liu W, Zhao S (2019) Novel risk stratification of de novo diffuse large B cell lymphoma based on tumour-infiltrating T lymphocytes evaluated by flow cytometry. Ann Hematol 98(2):391–399

    Article  CAS  PubMed  Google Scholar 

  10. Hui L, Chen Y (2015) Tumor microenvironment: sanctuary of the devil. Cancer Lett 368(1):7–13

    Article  CAS  PubMed  Google Scholar 

  11. Wu T, Dai Y(2017) Tumor microenvironment and therapeutic response. Cancer Lett 38761-68

  12. Solinas C, Ceppi M, Lambertini M, Scartozzi M, Buisseret L, Garaud S, Fumagalli D, de Azambuja E, Salgado R, Sotiriou C, Willard-Gallo K, Ignatiadis M (2017) Tumor-infiltrating lymphocytes in patients with HER2-positive breast cancer treated with neoadjuvant chemotherapy plus trastuzumab, lapatinib or their combination: a meta-analysis of randomized controlled trials. Cancer Treat Rev 57:8–15

    Article  CAS  PubMed  Google Scholar 

  13. Li J, Wang J, Chen R, Bai Y, Lu X (2017) The prognostic value of tumor-infiltrating T lymphocytes in ovarian cancer. Oncotarget 8(9):15621–15631

    Article  PubMed  PubMed Central  Google Scholar 

  14. Altan M, Pelekanou V, Schalper KA, Toki M, Gaule P, Syrigos K, Herbst RS, Rimm DL (2017) B7-H3 expression in NSCLC and its association with B7-H4, PD-L1 and tumor-infiltrating lymphocytes. Cli Cancer Res: Off J Am Assoc Cancer Res 23(17):5202–5209

    Article  CAS  Google Scholar 

  15. Miksch RC, Schoenberg MB, Weniger M, Bosch F, Ormanns S, Mayer B, Werner J, Bazhin AV, D'Haese JG (2019) Prognostic impact of tumor-infiltrating lymphocytes and neutrophils on survival of patients with upfront resection of pancreatic cancer. Cancers (Basel) 11(1):39

    Article  CAS  Google Scholar 

  16. Berntsson J, Nodin B, Eberhard J, Micke P, Jirstrom K (2016) Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer. Int J Cancer 139(5):1129–1139

    Article  CAS  PubMed  Google Scholar 

  17. Alikhan M, Song JY, Sohani AR, Moroch J, Plonquet A, Duffield AS, Borowitz MJ, Jiang L, Bueso-Ramos C, Inamdar K, Menon MP, Gurbuxani S, Chan E, Smith SM, Nicolae A, Jaffe ES, Gaulard P, Venkataraman G (2016) Peripheral T-cell lymphomas of follicular helper T-cell type frequently display an aberrant CD3(−/dim)CD4(+) population by flow cytometry: an important clue to the diagnosis of a Hodgkin lymphoma mimic. Modern Pathol: Off J United States Can Acad Pathol 29(10):1173–1182

    Article  CAS  Google Scholar 

  18. Singh A, Schabath R, Ratei R, Stroux A, Klemke CD, Nebe T, Florcken A, van Lessen A, Anagnostopoulos I, Dorken B, Ludwig WD, Pezzutto A, Westermann J (2014) Peripheral blood sCD3(−) CD4(+) T cells: a useful diagnostic tool in angioimmunoblastic T cell lymphoma. Hematol Oncol 32(1):16–21

    Article  CAS  PubMed  Google Scholar 

  19. Pizzolo G, Vinante F, Agostini C, Zambello R, Trentin L, Masciarelli M, Chilosi M, Benedetti F, Dazzi F, Todeschini G et al (1987) Immunologic abnormalities in angioimmunoblastic lymphadenopathy. Cancer 60(10):2412–2418

    Article  CAS  PubMed  Google Scholar 

  20. Schatton T, Scolyer RA, Thompson JF, Mihm MC Jr (2014) Tumor-infiltrating lymphocytes and their significance in melanoma prognosis. Methods Mol Biol (Clifton, NJ) 1102:287–324

    Article  CAS  Google Scholar 

  21. Yu PC, Long D, Liao CC, Zhang S (2018) Association between density of tumor-infiltrating lymphocytes and prognoses of patients with gastric cancer. Medicine 97(27):e11387

    Article  PubMed  PubMed Central  Google Scholar 

  22. Crickx E, Poullot E, Moulis G, Goulabchand R, Fieschi C, Galicier L, Meignin V, Coppo P, Delarue R, Casasnovas O, Roos-Weil D, de Leval L, Parrens M, Michel M, Dupuis J, Le Bras F, Fataccioli V, Martin-Garcia N, Godeau B, Haioun C, Gaulard P, Mahevas M (2019) Clinical spectrum, evolution, and management of autoimmune cytopenias associated with angioimmunoblastic T-cell lymphoma. Eur J Haematol 103(1):35–42

    Article  CAS  PubMed  Google Scholar 

  23. Choi CH, Park YH, Lim JH, Choi SJ, Kim L, Park IS, Han JY, Kim JM, Chu YC (2016) Prognostic implication of semi-quantitative Immunohistochemical assessment of CD20 expression in diffuse large B-cell lymphoma. J Pathol Transl Med 50(2):96–103

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bouaziz JD, Yanaba K, Venturi GM, Wang Y, Tisch RM, Poe JC, Tedder TF (2007) Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice. Proc Natl Acad Sci U S A 104(52):20878–20883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Crawford A, Macleod M, Schumacher T, Corlett L, Gray D (2006) Primary T cell expansion and differentiation in vivo requires antigen presentation by B cells. J Immunol (Baltimore, Md : 1950) 176(6):3498–3506

    Article  CAS  Google Scholar 

  26. Nielsen JS, Sahota RA, Milne K, Kost SE, Nesslinger NJ, Watson PH, Nelson BH (2012) CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Cli Cancer Res : Off J Am Assoc Cancer Res 18(12):3281–3292

    Article  CAS  Google Scholar 

  27. Hladikova K, Koucky V, Boucek J, Laco J, Grega M, Hodek M, Zabrodsky M, Vosmik M, Rozkosova K, Vosmikova H, Celakovsky P, Chrobok V, Ryska A, Spisek R, Fialova A (2019) Tumor-infiltrating B cells affect the progression of oropharyngeal squamous cell carcinoma via cell-to-cell interactions with CD8(+) T cells. J Immunother Cancer 7(1):261

    Article  PubMed  PubMed Central  Google Scholar 

  28. Xu X, Tan Y, Qian Y, Xue W, Wang Y, Du J, Jin L, Ding W (2019) Clinicopathologic and prognostic significance of tumor-infiltrating CD8+ T cells in patients with hepatocellular carcinoma: a meta-analysis. Medicine 98(2):e13923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schmidt M, Weyer-Elberich V, Hengstler JG, Heimes AS, Almstedt K, Gerhold-Ay A, Lebrecht A, Battista MJ, Hasenburg A, Sahin U, Kalogeras KT, Kellokumpu-Lehtinen PL, Fountzilas G, Wirtz RM, Joensuu H (2018) Prognostic impact of CD4-positive T cell subsets in early breast cancer: a study based on the FinHer trial patient population. Breast Cancer res: BCR 20(1):15

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Aberg JA, Kaplan JE, Libman H, Emmanuel P, Anderson JR, Stone VE, Oleske JM, Currier JS, Gallant JE (2009) Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV medicine Association of the Infectious Diseases Society of America. Clin Infect Dis: Off Publ Infect Dis Soc Am 49(5):651–681

    Article  Google Scholar 

  31. Clifford GM, Franceschi S (2009) Cancer risk in HIV-infected persons: influence of CD4(+) count. Future Oncol (London, England) 5(5):669–678

    Article  CAS  Google Scholar 

  32. Kitahata MM, Gange SJ, Abraham AG, Merriman B, Saag MS, Justice AC, Hogg RS, Deeks SG, Eron JJ, Brooks JT, Rourke SB, Gill MJ, Bosch RJ, Martin JN, Klein MB, Jacobson LP, Rodriguez B, Sterling TR, Kirk GD, Napravnik S, Rachlis AR, Calzavara LM, Horberg MA, Silverberg MJ, Gebo KA, Goedert JJ, Benson CA, Collier AC, Van Rompaey SE, Crane HM, McKaig RG, Lau B, Freeman AM, Moore RD (2009) Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 360(18):1815–1826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Huang H, Hao S, Li F, Ye Z, Yang J, Xiang J (2007) CD4+ Th1 cells promote CD8+ Tc1 cell survival, memory response, tumor localization and therapy by targeted delivery of interleukin 2 via acquired pMHC I complexes. Immunology 120(2):148–159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Oh S, Perera LP, Terabe M, Ni L, Waldmann TA, Berzofsky JA (2008) IL-15 as a mediator of CD4+ help for CD8+ T cell longevity and avoidance of TRAIL-mediated apoptosis. Proc Natl Acad Sci U S A 105(13):5201–5206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Crotty S(2011) Follicular helper CD4 T cells (TFH). Annu Rev Immunol 29621–663

  36. Judd J, Dulaimi E, Li T, Millenson MM, Borghaei H, Smith MR, Al-Saleem T (2017) Low level of blood CD4(+) T cells is an independent predictor of inferior progression-free survival in diffuse large B-cell lymphoma. Clin Lymphoma, Myeloma Leuk 17(2):83–88

    Article  Google Scholar 

  37. Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A, Ravoet M, Le Buanec H, Sibille C, Manfouo-Foutsop G, Veys I, Haibe-Kains B, Singhal SK, Michiels S, Rothe F, Salgado R, Duvillier H, Ignatiadis M, Desmedt C, Bron D, Larsimont D, Piccart M, Sotiriou C, Willard-Gallo K (2013) CD4(+) follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest 123(7):2873–2892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, Wunderlich JR, Somerville RP, Hogan K, Hinrichs CS, Parkhurst MR, Yang JC, Rosenberg SA (2014) Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344(6184):641–645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Javeed I, George W, Chao W, Andreas R, Gascoyne RD, Weisenburger DD, Greiner TC, Lynette S, Shuangping G, Wilcox RA (2014) Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood 123(19):2915

    Article  CAS  Google Scholar 

  40. Li B, Cui Y, Nambiar DK, Sunwoo JB, Li R (2019) The immune subtypes and landscape of squamous cell carcinoma. Cli Cancer Res: Off J Am Assoc Cancer Res 25(12):3528–3537

    CAS  Google Scholar 

  41. Danilova L, Ho WJ, Zhu Q, Vithayathil T, De Jesus-Acosta A, Azad NS, Laheru DA, Fertig EJ, Anders R, Jaffee EM, Yarchoan M (2019) Programmed cell death ligand-1 (PD-L1) and CD8 expression profiling identify an immunologic subtype of pancreatic ductal adenocarcinomas with favorable survival. Cancer Immunol Res 7(6):886–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Igarashi T, Takahashi H, Tobe T, Suzuki H, Mizoguchi K, Nakatsu HO, Ito H (2002) Effect of tumor-infiltrating lymphocyte subsets on prognosis and susceptibility to interferon therapy in patients with renal cell carcinoma. Urol Int 69(1):51–56

    Article  PubMed  Google Scholar 

  43. Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, Suzuki Y, Shintaku I, Nagura H, Ohtani H (2001) Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 61(13):5132–5136

    CAS  PubMed  Google Scholar 

  44. Savas P, Virassamy B, Ye C, Salim A, Mintoff CP, Caramia F, Salgado R, Byrne DJ, Teo ZL, Dushyanthen S, Byrne A, Wein L, Luen SJ, Poliness C, Nightingale SS, Skandarajah AS, Gyorki DE, Thornton CM, Beavis PA, Fox SB, Darcy PK, Speed TP, Mackay LK, Neeson PJ, Loi S (2018) Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med 24(7):986–993

    Article  CAS  PubMed  Google Scholar 

  45. Federico M, Rudiger T, Bellei M, Nathwani BN, Luminari S, Coiffier B, Harris NL, Jaffe ES, Pileri SA, Savage KJ, Weisenburger DD, Armitage JO, Mounier N, Vose JM (2013) Clinicopathologic characteristics of angioimmunoblastic T-cell lymphoma: analysis of the international peripheral T-cell lymphoma project. J Clin Oncol Off J Am Soc Clin Oncol 31(2):240–246

    Article  CAS  Google Scholar 

  46. Zain JM (2019) Aggressive T-cell lymphomas: 2019 updates on diagnosis, risk stratification, and management. Am J Hematol 94(8):929–946

    Article  CAS  PubMed  Google Scholar 

  47. Moskowitz AJ (2019) Practical treatment approach for Angioimmunoblastic T-cell lymphoma. J Oncol Pract 15(3):137–143

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (30900534) and the Sichuan Science and Technology Program (2018JY0612).

Author information

Authors and Affiliations

  1. Department of Pathology, West China Hospital of Sichuan University, No. 37 GuoXue Xiang, Sichuan, 610041, Chengdu, China

    Qiqi Zhu, Xueqin Deng, Wenqing Yao, Zihang Chen, Yunxia Ye, Limin Gao, Wenyan Zhang, Weiping Liu & Sha Zhao

Authors
  1. Qiqi Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xueqin Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenqing Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zihang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yunxia Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Limin Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenyan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Weiping Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sha Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.L and S.Z designed the study. S.Z, X.D, and Q.Z collected the data of flow cytometry. S.Z and Q.Z analysed and interpreted the data of flow cytometry. S.Z, W.L, Y.Y, L.G, and W.Z contributed to clinical data. Q.Z, Z.C, and W.Y contributed to the analysis and clinical data interpretation. S.Z and Q.Z wrote the paper. All authors contributed to the review, provided their comments on this manuscript, and approved the final version.

Corresponding author

Correspondence to Sha Zhao.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Supplementary Table 1

The subtype of aberrant phenotype of tumour cells in AITL. (DOCX 14 kb)

Supplementary Table 2

Clinical manifestation and laboratory examination data of patients with AITL. Abbreviations: HGB: Haemoglobin; RBC: Red blood cell; HCT: Haematocrit; RDW-CV: Red blood cell distribution width CV; MCHC: Mean concentration of haemoglobin in red blood cell; EO: Eosinophils; NEUT: Neutrophils; MONO: absolute count of monocytes; LYMPH: absolute count of lymphocytes; TP: Total protein; ALB: Albumin; GLB: Globulin; A/G: The ratio of albumin to globulin; GLU: Glucose; URIC: Uric acid; Cys-C: Cystatin-C; HDL: high-density lipoprotein; LDH: Lactate dehydrogenase; HBDH: Hydroxybutyrate dehydrogenase; CRP: C-reactive protein; PCT: Procalcitonin. (DOCX 16 kb)

Supplementary Table 3

Patient characteristics, according to TIL-Ts+Bs. (DOCX 27 kb)

Supplementary Table 4

Patient characteristics, according to TIL-Ts. (DOCX 27 kb)

Supplementary Table 5

Patient characteristics, according to TIL-Bs. (DOCX 27 kb)

Supplementary Table 6

Patient characteristics, according to CD4:CD8. (DOCX 27 kb)

Supplementary Table 7

Patient characteristics, according to TIL-related risk stratification. (DOCX 30 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, Q., Deng, X., Yao, W. et al. Novel tumour–infiltrating lymphocyte-related risk stratification based by flow cytometry for patients with de novo angioimmunoblastic T cell lymphoma. Ann Hematol 100, 715–723 (2021). https://doi.org/10.1007/s00277-020-04389-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-020-04389-5

Keywords

Search

Navigation