Tumor Microenvironment and Checkpoint Molecules in Primary Cutaneous Diffuse Large B-Cell Lymphoma—New Therapeutic Targets

Diffuse large B cell lymphoma (DLBCL), known as the most common non-Hodgkin lymphoma (NHL) subtype, is characterized by high clinical and biological heterogeneity. The tumor microenvironment (TME), in which the tumor cells reside, is crucial in the regulation of tumor initiation, progression, and metastasis, but it also has profound effects on therapeutic efficacy. The role of immune cells during DLBCL development is complex and involves reciprocal interactions between tumor cells, adaptive and innate immune cells, their soluble mediators and structural components present in the tumor microenvironment. Different immune cells are recruited into the tumor microenvironment and exert distinct effects on tumor progression and therapeutic outcomes. In this review, we focused on the role of macrophages, Neutrophils, T cells, natural killer cells and dendritic cells in the DLBCL microenvironment and their implication as target for DLBCL treatment. These new therapies, carried out by the induction of adaptive immunity through vaccination or passive of immunologic effectors delivery, enhance the ability of the immune system to react against the tumor antigens inducing the destruction of tumor cells.

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Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma

Haematologica ◽

10.3324/haematol.2019.243626 ◽

2020 ◽

pp. haematol.2019.243626 ◽

Cited By ~ 4

Author(s):

Matias Autio ◽

Suvi-Katri Leivonen ◽

Oscar Brück ◽

Satu Mustjoki ◽

Judit Mészáros Jørgensen ◽

...

Keyword(s):

Tumor Microenvironment ◽

B Cell ◽

Immune Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-20-1434 ◽

2020 ◽

Vol 26 (18) ◽

pp. 4823-4831 ◽

Cited By ~ 2

Author(s):

Rawan Faramand ◽

Michael Jain ◽

Verena Staedtke ◽

Hiroshi Kotani ◽

Renyuan Bai ◽

...

Keyword(s):

Tumor Microenvironment ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Large B Cell Lymphoma ◽

Large B Cell

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Prognostic Value of Epstein-Barr Virus (EBV)-Induced Gene 3 (EBI3) in Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-117970 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5411-5411

Author(s):

Hong Zheng ◽

Juan Huang

Keyword(s):

Tumor Microenvironment ◽

B Cell ◽

Tumor Cells ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Barr Virus ◽

Large B Cell Lymphoma ◽

Epstein Barr ◽

Large B Cell

Abstract Background: Epstein-Barr virus (EBV)-induced gene 3 (EBI3) as a subunit for heterodimeric cytokines IL-27 and IL-35, plays important roles both in regulation of T cell proliferation and Th1,Th2 and Th17 cells differentiation. EBI3 was closely related with tumor prognosis. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults with cure-rates of 40-60%. However, Relapse and refractory rate remain in 40% or so. In the present study, we aimed to detect the expression of EBI3 in DLBCL and to analyze its relationship with prognosis. Methods: We retrospective reviewed medical records of 51 newly diagnosed DLBCL patients in Sichuan People's Hospital between January 2010 and December 2016. Immunohistochemical (IHC) assay was used to detect the expression of EBI3 and PD-1 in DLBCL. The expression of CD5, CD30, Bcl-2, Bcl-6, C-myc and Epstein-Barr virus (EBV)-encoded RNAs (EBERs) in tumor specimens from 53 patients was also detected by IHC. The Kaplan-Meier method with log-rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis. Results: Of the 51 patients, 40 (78.4%) were EBI3-positive in tumor specimens. And PD-1 expression (39/40) was almost in parallel with EBI3 in tumor specimens. EBI3 expression was common in the non-germinal center B-cell-like (GCB) subtype than in the GCB subtype. Patients with EBI3 expression in tumor were more likely to be resistant to first-line chemotherapy when compared with the patients without EBI3 expression in tumor microenvironment (P <0.05). EBI3 expression in tumor microenvironment was correlated with PD-1 expression (r = − 0.20, P = 0.04). Only one patient with EBI3 expression was no PD-1 expression. No correlations were detected between EBI3 expression and the expression of EBER as well as other markers: ALK, CD5, c-Myc and CD30. The complete remission (CR) rates were 7.5% (3/40) and 71.4% in patients with and without EBI3 expression in tumor cells (P = 0.02). EBI3 expression in tumor cells was an independent risk predictor for ORR (P < 0.05). Conclusions: Our results indicate that EBI3 associated with poor prognosis and EBI3 may be a potential therapeutic target and prognosis marker. Disclosures No relevant conflicts of interest to declare.

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CD163+ Tumor Associated Macrophages Predict Inferior Outcome in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP

Blood ◽

10.1182/blood.v126.23.5023.5023 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5023-5023

Author(s):

Hong Zeng ◽

Yongqiang Wei ◽

Muchen Xie ◽

Lei Yang ◽

Fen Huang ◽

...

Keyword(s):

Tumor Microenvironment ◽

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

B Cell Lymphoma ◽

High Expression ◽

Tumor Associated Macrophages ◽

Large B Cell Lymphoma ◽

Cd163 Expression ◽

Large B Cell

Abstract Tumor-associated macrophages (TAMs), as the major component in tumor microenvironment, have been reported to correlate with the prognosis in diffuse large B-cell lymphoma (DLBCL). However due to the different subtypes of TAMs and the given therapy regimen, the prognostic value of TAMs in DLBCL patients remains controversial. To explore the prognostic significance of different TAMs subtypes in DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), we retrospectively analyzed 77 de novo DLBCL patients in present study. TAM markers including CD68 and CD163 were evaluated by immunohistochemistry. The cutoff value of CD68, CD163 and CD163/CD68 ratio was determined by receiver operating characteristic curve. In a total of 77 patients, CD68 high expression was found in71.4 %( 55/77) DLBCL patients and CD163 high expression in 51.4 %( 40/77 patients. Patients with high CD163 expression were more present with extranodal sites (P =0.049). However other clinical parameters including age, gender, Ann Arbor stage, performance stage, B symptoms, LDH and international prognostic index (IPI) showed no difference in patients with high and low CD68 or CD163 expression (P >0.05). CD68 expression has less effect on overall survival (OS) and event-free survival (EFS) (P =0.852, 0.782). However, high CD163 expression showed poor OS and EFS in DLBCL patients (P =0.006, 0.004) and also high CD163/CD68 ratio (P <0.001, 0.001). The multivariate analysis revealed that the high CD163 expression and CD163/CD68 ratio remained unfavorable factors for both OS (P =0.094, 0.002) and EFS (P =0.044, 0.016) independent of IPI. In conclusion, our date suggest that high CD163+ TAMs in tumor microenvironment may imply poor outcome in DLBCL patients treated with R-CHOP, but not CD68+ TAMs. Disclosures No relevant conflicts of interest to declare.

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Immunohistochemical Markers of Tumor Microenvironment as Prognostic Predictors in Diffuse Large B-Cell Lymphoma: Study from an Oncology Centre in South India

Asian Journal of Oncology ◽

10.1055/s-0040-1714305 ◽

2020 ◽

Author(s):

Indu R. Nair ◽

Athulya Sadeesh ◽

Pooja Phalak ◽

Pavithran Keechilat

Keyword(s):

Tumor Microenvironment ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cell Of Origin ◽

Chop Regimen ◽

Immunohistochemical Markers ◽

Stromal Microenvironment ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Introduction Diffuse large B-cell lymphoma (DLBCL) accounts for 60% of lymphomas in India. Although the survival of DLBCL patients has improved following the addition of rituximab, a subset of patients do not respond well to therapy. Among the several factors responsible for this varied response, tumor microenvironment is considered to be crucial. This study is a search for such prognostic markers in the tumor microenvironment. Materials and Methods A total of 97 patients were selected, of whom 34 were treated with the CHOP regimen and 63 with RCHOP. Immunohistochemistry for CD68 was performed to study the stromal-1 signature and CD34 for stromal-2 signature. Results There was a significant increase in the counts of CD68-positive cells among patients free of events. CD34 count was higher in patients with events in both CHOP and RCHOP groups. Conclusion Additional assessment of stromal microenvironment along with the cell of origin might predict the clinical outcome better in DLBCL.

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Abstract CT153: Pretreatment immunoscore and an inflamed tumor microenvironment (TME) are associated with efficacy in patients (Pts) with refractory large B cell lymphoma treated with axicabtagene ciloleucel (Axi-Cel) in ZUMA-1

10.1158/1538-7445.am2019-ct153 ◽

2019 ◽

Author(s):

John M. Rossi ◽

Jérôme Galon ◽

Edmund Chang ◽

Regis Perbost ◽

Nathalie Scholler ◽

...

Keyword(s):

Tumor Microenvironment ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Genes and Proteins Associated with the Tumor Microenvironment Are Differentially Expressed in Cured Versus Primary Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma.

Blood ◽

10.1182/blood.v110.11.3171.3171 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3171-3171

Author(s):

Johan Linderoth ◽

Patrik Edén ◽

Mats Ehinger ◽

Jeanette Valcich ◽

Mats Jerkeman ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

B Cell ◽

Mhc Class I ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Differentially Expressed ◽

Class I ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background: The aim of this study was to identify possible differences in gene expression profiles (GEP) between two clinically very different patient populations, cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma (DLBCL). Material and methods: Tumor samples from 37 patients with de novo DLBCL, stage II-IV, either in continuous primary complete remission (n=24) or with progressive disease during primary treatment (n=13) were selected from a larger study cohort and examined with respect to GEP using spotted 55K oligonucleotide arrays. Formalin fixed paraffin-embedded tissue for immunohistochemical analysis was available in 33 of 37 cases, and was used for confirmation on protein level. Results: The top 86 genes with the greatest statistical ability of discriminating the two patient groups were chosen for further analysis. Seventy-nine were over-expressed in the cured cohort, many of them coding for proteins expressed in the tumor microenvironment: CD68, several proteolytic enzymes and proteins involved in remodelling of extra cellular matrix and inflammation. Furthermore, MHC class I molecules, CD3δ, NK transcript 4, and ICAM-1 were overexpressed indicating an enhanced immunological reaction. Immunohistochemistry showed that the frequency of cells expressing CD68, defining the macrophage population, was higher in the cured cohort and that expression of lysozyme, cathepsin D, UPAR, and ICAM-1, was mainly seen within the reactive cells. Tumor infiltrating CD8+ T-cells were more frequent within the cured cohort, corresponding to the increased MHC class I expression seen within this group. Conclusions: In DLBCL, genes coding for antigens present in the tumor microenvironment are differentially expressed in patients with cured vs. chemotherapy-refractory disease. Our findings suggest that a reactive microenvironment, including tumor infiltrating T-cells and macrophages, may have impact on outcome of chemotherapy in DLBCL.

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