Prognostic Relevance of Tumor-infiltrating CD4 Cells and Total Metabolic Tumor Volume-based Risk Stratification in Diffuse Large B-cell Lymphoma

Overview

Journal Haematologica

Specialty Hematology

Date 2024 Apr 4

PMID 38572548

Authors

Daisuke Ikeda

Mitsuaki Oura

Atsushi Uehara

Rikako Tabata

Kentaro Narita

Masami Takeuchi

Youichi Machida

Kosei Matsue

Affiliations

Soon will be listed here.

Abstract

In order to elucidate the relationship between pretreatment radiomic parameters and the proportions of various tumor-infiltrating (TI) cells, we retrospectively analyzed the association of total metabolic tumor volume (TMTV) and TI cells on biopsied tumor lesions in 171 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). The surface markers of TI cells were analyzed by multicolor flow cytometry using a dissected single-cell suspension. In examining the correlation between TI cells and positron-emission tomography-derived parameters (maximum standardized uptake value [SUVmax], total metabolic tumor volume [TMTV], and total lesion glycolysis), intratumoral cell types minimally influenced the results, except for a weak negative correlation between CD4+ cells and SUVmax (R=-0.16, P=0.045). Even for the lesion fluorodeoxyglucose uptake at the biopsied site, CD19+ cells (indicative of malignant burden) showed only a weak correlation with the highest SUV (R=0.21, P=0.009), whereas CD3+ (R=-0.25, P=0.002) and CD4+ cells (R=-0.29, P<0.001) demonstrated a similarly weak inverse correlation. High TMTV and low TI CD4+ cells were independently associated with poor prognosis and their combination identified the most adverse population (3-year progression-free survival: 32.3%, 95% confidence interval [CI]: 19.4-53.7; 3-year overall survival: 48.4%, 95% CI: 33.6-69.6). Moreover, radiomic parameters incorporating the international prognostic index significantly improved the 3-year survival prediction (area under the curve: 0.76, P<0.05) compared to their standalone use. This study underscores the prognostic impact of TI CD4+ cells on DLBCL and suggests that integration of TMTV and TI cell analysis enhances the accuracy of prognostic prediction.

References

Chapuy B, Stewart C, Dunford A, Kim J, Kamburov A, Redd R . Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018; 24(5):679-690. PMC: 6613387. DOI: 10.1038/s41591-018-0016-8. View

Zhou Z, Sehn L, Rademaker A, Gordon L, LaCasce A, Crosby-Thompson A . An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2013; 123(6):837-42. PMC: 5527396. DOI: 10.1182/blood-2013-09-524108. View

Eude F, Toledano M, Vera P, Tilly H, Mihailescu S, Becker S . Reproducibility of Baseline Tumour Metabolic Volume Measurements in Diffuse Large B-Cell LymphomA: Is There a Superior Method?. Metabolites. 2021; 11(2). PMC: 7911393. DOI: 10.3390/metabo11020072. View

Sehn L, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P . The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2006; 109(5):1857-61. DOI: 10.1182/blood-2006-08-038257. View

Huang B, Chan T, Kwong D, Chan W, Khong P . Nasopharyngeal carcinoma: investigation of intratumoral heterogeneity with FDG PET/CT. AJR Am J Roentgenol. 2012; 199(1):169-74. DOI: 10.2214/AJR.11.7336. View

Leivonen S, Pollari M, Bruck O, Pellinen T, Autio M, Karjalainen-Lindsberg M . T-cell inflamed tumor microenvironment predicts favorable prognosis in primary testicular lymphoma. Haematologica. 2018; 104(2):338-346. PMC: 6355505. DOI: 10.3324/haematol.2018.200105. View

Le Goff E, Blanc-Durand P, Roulin L, Lafont C, Loyaux R, MBoumbae D . Baseline circulating tumour DNA and total metabolic tumour volume as early outcome predictors in aggressive large B-cell lymphoma. A real-world 112-patient cohort. Br J Haematol. 2023; 202(1):54-64. DOI: 10.1111/bjh.18809. View

George Mikhaeel N, Heymans M, Eertink J, de Vet H, Boellaard R, Duhrsen U . Proposed New Dynamic Prognostic Index for Diffuse Large B-Cell Lymphoma: International Metabolic Prognostic Index. J Clin Oncol. 2022; 40(21):2352-2360. PMC: 9287279. DOI: 10.1200/JCO.21.02063. View

Kataoka K, Miyoshi H, Sakata S, Dobashi A, Couronne L, Kogure Y . Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas. Leukemia. 2019; 33(7):1687-1699. PMC: 6755969. DOI: 10.1038/s41375-019-0380-5. View

10.

Keane C, Gill D, Vari F, Cross D, Griffiths L, Gandhi M . CD4(+) tumor infiltrating lymphocytes are prognostic and independent of R-IPI in patients with DLBCL receiving R-CHOP chemo-immunotherapy. Am J Hematol. 2013; 88(4):273-6. DOI: 10.1002/ajh.23398. View

11.

Nanni C, Kobe C, Baessler B, Baues C, Boellaard R, Borchmann P . European Association of Nuclear Medicine (EANM) Focus 4 consensus recommendations: molecular imaging and therapy in haematological tumours. Lancet Haematol. 2023; 10(5):e367-e381. DOI: 10.1016/S2352-3026(23)00030-3. View

12.

Sehn L, Salles G . Diffuse Large B-Cell Lymphoma. N Engl J Med. 2021; 384(9):842-858. PMC: 8377611. DOI: 10.1056/NEJMra2027612. View

13.

Rojek A, Kline J, Feinberg N, Appelbaum D, Pu Y, Derman B . Optimization of Metabolic Tumor Volume as a Prognostic Marker in CAR T-Cell Therapy for Aggressive Large B-cell NHL. Clin Lymphoma Myeloma Leuk. 2023; 24(2):83-93. DOI: 10.1016/j.clml.2023.09.005. View

14.

Coutinho R, Clear A, Mazzola E, Owen A, Greaves P, Wilson A . 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. Haematologica. 2014; 100(3):363-9. PMC: 4349275. DOI: 10.3324/haematol.2014.110189. View

15.

Autio M, Leivonen S, Bruck O, Mustjoki S, Jorgensen J, Karjalainen-Lindsberg M . Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma. Haematologica. 2020; 106(3):718-729. PMC: 7927991. DOI: 10.3324/haematol.2019.243626. View

16.

Tamma R, Ranieri G, Ingravallo G, Annese T, Oranger A, Gaudio F . Inflammatory Cells in Diffuse Large B Cell Lymphoma. J Clin Med. 2020; 9(8). PMC: 7463675. DOI: 10.3390/jcm9082418. View

17.

Eertink J, Zwezerijnen G, Heymans M, Pieplenbosch S, Wiegers S, Duhrsen U . Baseline PET radiomics outperforms the IPI risk score for prediction of outcome in diffuse large B-cell lymphoma. Blood. 2023; 141(25):3055-3064. PMC: 10646814. DOI: 10.1182/blood.2022018558. View

18.

Autio M, Leivonen S, Bruck O, Karjalainen-Lindsberg M, Pellinen T, Leppa S . Clinical Impact of Immune Cells and Their Spatial Interactions in Diffuse Large B-Cell Lymphoma Microenvironment. Clin Cancer Res. 2021; 28(4):781-792. PMC: 9377736. DOI: 10.1158/1078-0432.CCR-21-3140. View

19.

Xu Y, Kroft S, McKenna R, Aquino D . Prognostic significance of tumour-infiltrating T lymphocytes and T-cell subsets in de novo diffuse large B-cell lymphoma: a multiparameter flow cytometry study. Br J Haematol. 2001; 112(4):945-9. DOI: 10.1046/j.1365-2141.2001.02649.x. View

20.

Jiang Y, Li Y, Zhu B . T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015; 6:e1792. PMC: 4669840. DOI: 10.1038/cddis.2015.162. View