The microenvironment of diffuse large B-cell lymphoma (DLBCL) is composed of various components, including immune cells and immune checkpoints, some of which have been correlated with the prognosis of DLBCL, but their results remain controversial. Therefore, we conducted a systematic review and meta-analysis to investigate the association between the microenvironment and prognosis in DLBCL. We searched PubMed, Web of Science, and EMBASE for relevant articles between 2001 and 2022. Twenty-five studies involving 4495 patients with DLBCL were included in the analysis. This meta-analysis confirmed that high densities of Foxp3+Tregs and PD-1+T cells are good indicators for overall survival (OS) in DLBCL, while high densities of programmed cell death protein ligand1(PD-L1)-positive expression cells and T-cell immunoglobulin-and mucin domain-3-containing molecule 3 (TIM-3)-positive expression tumor-infiltrating cells (TILs) play a contrary role in OS. Additionally, higher numbers of T-cell intracytoplasmic antigen-1(TIA-1)-positive expression T cells imply better OS and progression-free survival (PFS), while high numbers of lymphocyte activation gene(LAG)-positive expression TILs predict bad OS and PFS. Various non-tumoral cells in the microenvironment play important roles in the prognosis of DLBCL.
SiegelRLMillerKDJemalA.Cancer statistics, 2019. CA Cancer J Clin2019; 69: 7-34.
2.
GuoLLinPXiongH, et al. Molecular heterogeneity in diffuse large B-cell lymphoma and its implications in clinical diagnosis and treatment. Biochim Biophys Acta Rev Cancer2018; 1869: 85-96.
3.
KlenerPKlanovaM.Drug resistance in Non-Hodgkin Lymphomas. Int J Mol Sci2020; 21(6): 2081.
4.
ZhangJGuYChenB.Drug-resistance mechanism and new targeted drugs and treatments of relapse and refractory DLBCL. Cancer Manag Res2023; 15: 245-255.
5.
TillyHMorschhauserFSehnLH, et al. Polatuzumab vedotin in previously untreated diffuse large b-cell lymphoma. N Engl J Med2022; 386: 351-363.
6.
ChapuyBStewartCDunfordAJ, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med2018; 24: 679-690.
7.
SchmitzRWrightGWHuangDW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med2018; 378: 1396-1407.
8.
WrightGWHuangDWPhelanJD, et al. A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer Cell2020; 37: 551-568.e514.
9.
A predictive model for aggressive non-Hodgkin’s lymphoma. New Engl J1993; 329: 987–994.
10.
KotlovNBagaevARevueltaMV, et al. Clinical and biological subtypes of B-cell lymphoma revealed by microenvironmental signatures. Cancer Discov2021; 11: 1468-1489.
11.
KlineJGodfreyJAnsellSM.The immune landscape and response to immune checkpoint blockade therapy in lymphoma. Blood2020; 135: 523-533.
12.
KumarDXuML.Microenvironment cell contribution to lymphoma immunity. Front Oncol2018; 8: 288.
13.
HopkenUERehmA.Targeting the tumor microenvironment of leukemia and lymphoma. Trends Cancer2019; 5: 351-364.
14.
PengFQinYMuS, et al. Prognostic role of regulatory T cells in lymphoma: a systematic review and meta-analysis. J Cancer Res Clin Oncol2020; 146: 3123-3135.
15.
AutioMLeivonenSKBrückO, et al. Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma. Haematologica2021; 106: 718-729.
16.
SongJYNwangwuMHeTF, et al. Low T-cell proportion in the tumor microenvironment is associated with immune escape and poor survival in diffuse large B-cell lymphoma. Haematologica2023; 108: 2167-2177.
17.
ShenRXuPPWangN, et al. Influence of oncogenic mutations and tumor microenvironment alterations on extranodal invasion in diffuse large B-cell lymphoma. Clin Transl Med2020; 10: e221.
18.
YeXWangLNieM, et al. A single-cell atlas of diffuse large B cell lymphoma. Cell Rep2022; 39: 110713.
19.
AutioMLeivonenSKBrückO, et al. Clinical impact of immune cells and their spatial interactions in diffuse large B-cell lymphoma microenvironment. Clin Cancer Res2022; 28: 781-792.
20.
CioroianuAIStingaPISticlaruL, et al. Tumor microenvironment in diffuse large B-cell lymphoma: role and prognosis. Anal Cell Pathol (Amst)2019; 2019: 8586354.
21.
GhorabDSHelalyAMEl MahdiHS, et al. Prognostic role of tumor microenvironment in DLBCL and relation to patients' clinical outcome: a clinical and immunohistochemical study. Anal Cell Pathol (Amst)2022; 2022: 9993496.
22.
ZhuYFuDShiQ, et al. Oncogenic mutations and tumor microenvironment alterations of older patients with diffuse large B-cell lymphoma. Front Immunol2022; 13: 842439.
23.
TakaharaTNakamuraSTsuzukiT, et al. The immunology of DLBCL. Cancers (Basel)2023; 15(3): 835.
24.
de GrootFAde GroenRALvan den BergA, et al. Biological and clinical implications of gene-expression profiling in diffuse large B-cell lymphoma: a proposal for a targeted BLYM-777 consortium panel as part of a multilayered analytical approach. Cancers (Basel)2022; 14(8): 1857.
25.
OpintoGVeglianteMCNegriA, et al. The tumor microenvironment of DLBCL in the computational era. Front Oncol2020; 10: 351.
26.
Xu-MonetteZYWeiLFangX, et al. Genetic subtyping and phenotypic characterization of the immune microenvironment and MYC/BCL2 double expression reveal heterogeneity in diffuse large B-cell lymphoma. Clin Cancer Res2022; 28: 972-983.
27.
SteenCBLucaBAEsfahaniMS, et al. The landscape of tumor cell states and ecosystems in diffuse large B cell lymphoma. Cancer Cell2021; 39: 1422-1437.e1410.
28.
WangLYuanWLiL, et al. Immunogenomic-based analysis of hierarchical clustering of diffuse large cell lymphoma. J Immunol Res2022; 2022: 9544827.
29.
MaSYTianXPCaiJ, et al. A prognostic immune risk score for diffuse large B-cell lymphoma. Br J Haematol2021; 194: 111-119.
30.
YangJYuLManJ, et al. Immune scoring model based on immune cell infiltration to predict prognosis in diffuse large B-cell lymphoma. Cancer2022; 129: 235-244.
31.
JiangYSunHXuH, et al. Immunophenotypic landscape and prognosis-related mRNA Signature in Diffuse Large B Cell Lymphoma. Front Genet2022; 13: 872001.
32.
LiangXJFuRYWangHN, et al. An immune-related prognostic classifier is associated with diffuse large B cell lymphoma microenvironment. J Immunol Res2021; 2021: 5564568.
33.
MerdanSSubramanianKAyerT, et al. Gene expression profiling-based risk prediction and profiles of immune infiltration in diffuse large B-cell lymphoma. Blood Cancer J2021; 11: 2.
34.
TaylorCRLevensonRM.Quantification of immunohistochemistry–issues concerning methods, utility and semiquantitative assessment II. Histopathology2006; 49: 411-424.
35.
BatraUNathanySSharmaM, et al. IHC versus FISH versus NGS to detect ALK gene rearrangement in NSCLC: all questions answered?J Clin Pathol2022; 75: 405-409.
TanWCCNerurkarSNCaiHY, et al. Overview of multiplex immunohistochemistry/immunofluorescence techniques in the era of cancer immunotherapy. Cancer Commun (Lond)2020; 40: 135-153.
38.
SamowitzWSweeneyCHerrickJ, et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res2005; 65: 6063-6069.
39.
GoldingBLuuAJonesR, et al. The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC). Mol Cancer2018; 17: 52.
40.
HanahanDCoussensLM.Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell2012; 21: 309-322.
41.
VitaleIManicGCoussensLM, et al. Macrophages and metabolism in the tumor microenvironment. Cell Metab2019; 30: 36-50.
FinicleBTJayashankarVEdingerAL.Nutrient scavenging in cancer. Nat Rev Cancer2018; 18: 619-633.
44.
VijayanDYoungATengMWL, et al. Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer2017; 17: 709-724.
45.
ScharpingNEDelgoffeGM.Tumor microenvironment metabolism: a new checkpoint for anti-tumor immunity. Vaccines (Basel)2016; 4(4): 46.
46.
DuanQZhangHZhengJ, et al. Turning cold into hot: firing up the tumor microenvironment. Trends Cancer2020; 6: 605-618.
47.
ShiYDengLSongY, et al. CD3+/CD8+ T-cell density and tumoral PD-L1 predict survival irrespective of rituximab treatment in Chinese diffuse large B-cell lymphoma patients. Int J Hematol2018; 108: 254-266.
48.
AnsellSMStensonMHabermannTM, et al. CD4+T-cell immune response to large B-cell non-Hodgkin's lymphoma predicts patient outcome. J Clin Oncol2001; 19: 720-726.
49.
LinderothJEhingerMJerkemanM, et al. CD40 expression identifies a prognostically favourable subgroup of diffuse large B-cell lymphoma. Leuk Lymphoma2007; 48: 1774-1779.
50.
AutioMLeivonenSKBrückO, et al. Clinical impact of immune cells and their spatial interactions in diffuse large B-cell lymphoma microenvironment. Clin Cancer Res2022; 28: 781-792.
51.
HuLYXuXLRaoHL, et al. Expression and clinical value of programmed cell death-ligand 1 (PD-L1) in diffuse large B cell lymphoma: a retrospective study. Chin J Cancer2017; 36: 94.
52.
GuQHLiJChenZL, et al. Expression and prognostic significance of PD-L2 in diffuse large B-cell lymphoma. Front Oncol2021; 11: 664032.
53.
ZhaoYCuiWLFengZY, et al. Expression of Foxp3 and interleukin-7 receptor and clinicopathological characteristics of patients with diffuse large B-cell lymphoma. Oncology Letters2020; 19: 2755-2764.
54.
AhearneMJBhullerKHewR, et al. Expression of PD-1 (CD279) and FoxP3 in diffuse large B-cell lymphoma. Virchows Archiv2014; 465: 351-358.
55.
ZhangTRenTSongZ, et al. Genetic mutations of Tim-3 ligand and exhausted Tim-3(+) CD8(+) T cells and survival in diffuse large B cell lymphoma. J Immunol Res2020; 2020: 6968595.
56.
CarrerasJKikutiYYHiraiwaS, et al. High PTX3 expression is associated with a poor prognosis in diffuse large B-cell lymphoma. Cancer Sci2022; 113: 334-348.
57.
AutioMLeivonenSKBrückO, et al. Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma. Haematologica2021; 106: 718-729.
58.
JeongJOhEJYangWI, et al. Implications of infiltrating immune cells within bone marrow of patients with diffuse large B-cell lymphoma. Hum Pathol2017; 64: 222-231.
59.
NamSJGoHPaikJH, et al. An increase of M2 macrophages predicts poor prognosis in patients with diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. Leuk Lymphoma2014; 55: 2466-2476.
60.
Serag El-DienMMAbdouAGAsaadNY, et al. Intratumoral FOXP3+ regulatory T cells in diffuse large B-cell lymphoma. App Immunohist Molecular Morphol2017; 25: 534-542.
61.
KeaneCLawSCGouldC, et al. LAG3: A novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma. Blood Advances2020; 4: 1367-1377.
62.
BerndHWZiepertMThornsC, et al. Loss of HLA-DR expression and immunoblastic morphology predict adverse outcome in diffuse large B-cell lymphoma - Analyses of cases from two prospective randomized clinical trials. Haematologica2009; 94: 1569-1580.
63.
MatsukiEBohnOLEl JamalS, et al. Lymphocyte-to-monocyte ratio may serve as a better prognostic indicator than tumor-associated macrophages in DLBCL treated with rituximab. Appl Immunohistochem Mol Morphol2019; 27: 572-580.
64.
HasselblomSSigurdadottirMHanssonU, et al. The number of tumour-infiltrating TIA-1+ cytotoxic T cells but not FOXP3+ regulatory T cells predicts outcome in diffuse large B-cell lymphoma. Br J Haematol2007; 137: 364-373.
65.
LiLSunRFMiaoY, et al. PD-1/PD-L1 expression and interaction by automated quantitative immunofluorescent analysis show adverse prognostic impact in patients with diffuse large B-cell lymphoma having T-cell infiltration: a study from the International DLBCL Consortium Program. Mod Pathol2019; 32: 741-754.
66.
van ImhoffGWBoermaEJGvan der HoltB, et al. Prognostic impact of germinal center-associated proteins and chromosomal breakpoints in poor-risk diffuse large B-cell lymphoma. J Clin Oncol2006; 24: 4135-4142.
67.
IshikawaENakamuraMShimadaK, et al. Prognostic impact of PD-L1 expression in primary gastric and intestinal diffuse large B-cell lymphoma. J Gastroenterol2020; 55: 39-50.
68.
Gomez-GelvezJCSalamaMEPerkinsSL, et al. Prognostic impact of tumor microenvironment in diffuse large B-cell lymphoma uniformly treated with R-CHOP chemotherapy. Am J Clin Pathol2016; 145: 514-523.
69.
RiihijärviSFiskvikITaskinenM, et al. Prognostic influence of macrophages in patients with diffuse large B-Cell lymphoma: A correlative study from a nordic phase ii trial. Haematologica2015; 100: 238-245.
70.
CoutinhoRClearAJMazzolaE, et al. Revisiting the immune microenvironment of diffuse large B-cell lymphoma using a tissue microarray and immunohistochemistry: Robust semi-automated analysis reveals CD3 and FoxP3 as potential predictors of response to R-CHOP. Haematologica2015; 100: 363-369.
71.
CrociGAAu-YeungRKHReinkeS, et al. SPARC-positive macrophages are the superior prognostic factor in the microenvironment of diffuse large B-cell lymphoma and independent of MYC rearrangement and double-/triple-hit status. Ann Oncol2021; 32: 1400-1409.
72.
LeeSKimDHOhSY, et al. Clinicopathologic significance of tumor microenvironment CD11c, and FOXP3 expression in diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, anthracycline, vincristine, and prednisone (R-CHOP) combination chemotherapy. Kor J Internal Med2017; 32: 335-344.
73.
KimSNamSJParkC, et al. High tumoral PD-L1 expression and low PD-1+ or CD8+ tumor-infiltrating lymphocytes are predictive of a poor prognosis in primary diffuse large B-cell lymphoma of the central nervous system. OncoImmunology2019; 8(9): e1626653.
74.
WadaNZakiMAHoriY, et al. Tumour-associated macrophages in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group. Histopathology2012; 60: 313-319.
75.
YuHFuDXuPP, et al. Implication of immune cell signature of tumor microenvironment in diffuse large B-cell lymphoma. Hematol Oncol2021; 39: 616-624.
76.
WangGQiuCZhangC, et al. Construction of a DLBCL prognostic signature based on tumor microenvironment. Expert Rev Hematol2021; 14: 679-686.
77.
McShaneLMAltmanDGSauerbreiW, et al. REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer2005; 93: 387-391.
78.
JulianPTHigginsThompsonSGDeeksJJ, et al. Mea-suring inconsistency in meta-analyses. BMJ2003; 327: 557-560.
79.
LeivonenSKPollariMBruckO, et al. T-cell inflamed tumor microenvironment predicts favorable prognosis in primary testicular lymphoma. Haematologica2019; 104: 338-346.
80.
YangZZNovakAJZiesmerSC, et al. Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin's lymphoma. Cancer Res2006; 66: 10145-10152.
81.
FelchtMHeckMWeissC, et al. Expression of the T-cell regulatory marker FOXP3 in primary cutaneous large B-cell lymphoma tumour cells. Brit J Dermatol2012; 167: 348-358.
82.
HorladHMaCYanoH, et al. An IL-27/Stat3 axis induces expression of programmed cell death 1 ligands (PD-L1/2) on infiltrating macrophages in lymphoma. Cancer Sci2016; 107: 1696-1704.
83.
HeJChenZXueQ, et al. Identification of molecular subtypes and a novel prognostic model of diffuse large B-cell lymphoma based on a metabolism-associated gene signature. J Transl Med2022; 20: 186.
84.
XerriLHuetSVenstromJM, et al. Rituximab treatment circumvents the prognostic impact of tumor-infiltrating T-cells in follicular lymphoma patients. Hum Pathol2017; 64: 128-136.
85.
FridmanWHZitvogelLSautès–FridmanC, et al. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol2017; 14: 717-734.
86.
GalonJCostesASanchez-CaboF, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science2006; 313: 1960-1964.
87.
RajnaiHHeyningFHKoensL, et al. The density of CD8+ T-cell infiltration and expression of BCL2 predicts outcome of primary diffuse large B-cell lymphoma of bone. Virchows Arch2014; 464: 229-239.
88.
MooreDCPeeryMRTobonKA, et al. New and emerging therapies for the treatment of relapsed/refractory diffuse large B-cell lymphoma. J Oncol Pharm Pract2022; 28: 1848-1858.
89.
FarinhaPAl-TourahAGillK, et al. The architectural pattern of FOXP3-positive T cells in follicular lymphoma is an independent predictor of survival and histologic transformation. Blood2010; 115: 289-295.
90.
McGuiganAJColemanHGMcCainRS, et al. Immune cell infiltrates as prognostic biomarkers in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis. J Pathol Clin Res2021; 7: 99-112.
91.
XieMJiangQZhaoS, et al. Prognostic value of tissue-infiltrating immune cells in tumor microenvironment of follicular lymphoma: A meta-analysis. Int Immunopharmacol2020; 85: 106684.
92.
BenseRDSotiriouCPiccart-GebhartMJ, et al. Releva-nce of Tumor-Infiltrating Immune Cell Composition and Functionality for Disease Outcome in Breast Cancer. J Natl Cancer Inst2017; 109(1): djw192.
93.
Sautes-FridmanCLawandMGiraldoNA, et al. Tertiary Lymphoid Structures in Cancers: Prognostic Value, Regulation, and Manipulation for Therapeutic Intervention. Front Immunol2016; 7: 407.
94.
ZhaoDMThorntonAMDiPaoloRJ, et al. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood2006; 107: 3925-3932.
95.
MittalSMarshallNADuncanL, et al. Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma. Blood2008; 111: 5359-5370.
96.
WangXHongYMengS, et al. A novel immune-related epigenetic signature based on the transcriptome for predicting the prognosis and therapeutic response of patients with diffuse large B-cell lymphoma. Clin Immunol2022; 243: 109105.
97.
HasselblomSHanssonUSigurdardottirM, et al. Expression of CD68+ tumor-associated macrophages in patients with diffuse large B-cell lymphoma and its relation to prognosis. Pathol Int2008; 58: 529-532.
GlennieMJFrenchRRCraggMS, et al. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol2007; 44: 3823-3837.
100.
SmeltzerJPJonesJMZiesmerSC, et al. Pattern of CD14+ follicular dendritic cells and PD1+ T cells independently predicts time to transformation in follicular lymphoma. Clin Cancer Res2014; 20: 2862-2872.
101.
KatzenbergerTOttGKleinT, et al. Cytogenetic alterations affecting BCL6 are predominantly found in follicular lymphomas grade 3B with a diffuse large B-cell component. Am J Pathol2004; 165: 481-490.
102.
AokiTChongLCTakataK, et al. Single-cell transcriptome analysis reveals disease-defining t-cell subsets in the tumor microenvironment of classic hodgkin lymphoma. Cancer Discov2020; 10: 406-421.
103.
MaruhashiTOkazakiIMSugiuraD, et al. LAG-3 inhibits the activation of CD4(+) T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII. Nat Immunol2018; 19: 1415-1426.
104.
HeYYuHRozeboomL, et al. LAG-3 protein expression in non-small cell lung cancer and its relationship with PD-1/PD-L1 and tumor-infiltrating lymphocytes. J Thorac Oncol2017; 12: 814-823.
105.
Wei-WeiDengLiangMaoGuang-TaoYu, et al. LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma. Oncoimmunology2016; 5: e1239005.
106.
GiraldoNABechtEPagesF, et al. Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin Cancer Res2015; 21: 3031-3040.
107.
JiangJJinMSKongF, et al. Decreased galectin-9 and increased Tim-3 expression are related to poor prognosis in gastric cancer. PLoS One2013; 8: e81799.
108.
ZhuangXZhangXXiaX, et al. Ectopic expression of TIM-3 in lung cancers: a potential independent prognostic factor for patients with NSCLC. Am J Clin Pathol2012; 137: 978-985.
109.
ChenBJDashnamoorthyRGaleraP, et al. The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma. Oncotarget2019; 10(21): 2030-2040.
110.
DuWYangMTurnerA, et al. TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action. Int J Mol Sci2017; 18(3): 645.
111.
MitteldorfCBerishaAPfaltzMC, et al. Tumor microenvironment and checkpoint molecules in primary cutaneous diffuse large B-cell lymphoma-new therapeutic targets. Am J Surg Pathol2017; 41(7): 998-1004.
112.
WangLLiLRYoungKH.New agents and regimens for diffuse large B cell lymphoma. J Hematol Oncol2020; 13: 175.
113.
ModiDPotugariBUbertiJ.Immunotherapy for diffuse large B-cell lymphoma: current landscape and future directions. Cancers2021; 13(22): 5827.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
