Clinical Impact of Immune Cells and Their Spatial Interactions in Diffuse Large B-Cell Lymphoma Microenvironment

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.

Download Full-text

Gene Expression Signature of Host Immune Response Is Predictive of Follicular Lymphoma Patient Survival in Independent Cohorts, and Correlates with Transformation to Diffuse Large B-Cell Lymphoma.

Blood ◽

10.1182/blood.v114.22.2951.2951 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2951-2951

Author(s):

Ash A Alizadeh ◽

Andrew J Gentles ◽

Sylvia K Plevritis ◽

Ronald Levy

Keyword(s):

Gene Expression ◽

Immune Response ◽

Follicular Lymphoma ◽

B Cell ◽

Immune Cells ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell ◽

Independent Cohort

Abstract Abstract 2951 Poster Board II-927 Background: Expression signatures of infiltrating immune cells [1] have been shown to predict survival in follicular lymphoma (FL), but have not been cross-validated in independent patient cohorts [2,3]. These signatures may relate biologically to the frequency of infiltrating including T-cells and macrophages, or to specific transcription programs within tumor cells and/or the tumor microenvironment. We sought to evaluate the validity of this model in an independent cohort of patients with FL, assessing its relationship to outcomes including histological transformation and death. Methods: The immune response (IR) predictor score proposed by Dave et al. [1] was applied to gene expression data from an independent cohort of 88 FL patients [4] with known survival outcomes and history of transformation to diffuse large B-cell lymphoma (DLBCL). Genes (n=66) corresponding to IR1 and IR2 signatures were mapped from Affymetrix microarrays [1] to a custom cDNA array [4] via Entrez Gene ID, and the composite IR score was calculated per the scheme proposed by Dave et al. Results: The IR score was predictive of patient outcome in the 88 patient test set as a continuous variable (p=0.001, HR=2.01, 95% CI 0.50-1.30). Partitioning of patients into high and low risk groups based on the median IR score across the cohort robustly separated survival curves (Figure A). The IR score was significantly higher in FL patients known to undergo transformation to DLBCL (Figure B: mean IR score of -0.6 in non-transforming FL vs. -0.2 in transforming FL; p∼10-11, t-test). Conclusions: The IR score of Dave et al. was highly significant as a predictor of survival in the independent patient cohort [4]. Moreover, the score was significantly associated with propensity of FL to transform to DLBCL. To our knowledge, immune cell infiltration has not previously been implicated in transformation. 1. Dave SS et al. (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351(21): 2159-2169. 2. Tibshirani R (2005) Immune signatures in follicular lymphoma. N Engl J Med 352: 1496-1497. 3. Chu G Hong WJ, Warnke R, Chu G (2005). Immune Signatures in Follicular Lymphoma (Corres). N Engl J Med. 352: 1496-1497. 4. Glas AM et al. (2005) Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment. Blood 105(1): 301-307. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

The Impact of Activated Akt Expression On Clinical Outcome in Diffuse Large B-Cell Lymphoma: A Clinicopathological Study of 99 Cases.

Blood ◽

10.1182/blood.v120.21.2676.2676 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2676-2676

Author(s):

Jung Yong Hong ◽

Moon Ki Choi ◽

Young Saing Kim ◽

Chi Hoon Maeng ◽

Su Jin Lee ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Clinical Impact ◽

Free Survival ◽

Large B Cell Lymphoma ◽

The Impact ◽

Large B Cell

Abstract Abstract 2676 Purpose Akt is a serine/threonine kinase that plays a central role in cell proliferation and growth. To define clinical impact of Akt expression in diffuse large B-cell lymphoma(DLBCL), we investigated the expression of phospho-Akt(p-Akt) in DLBCL and analyzed clinical impact of p-Akt expression on patient survival. Methods We evaluated the p-Akt expression in 99 DLBCL patients using tissue microarray(TMA) technology. Results Positive p-Akt expression was observed in 15.2% of the patients and significantly associated with elevated lactic dehydrogenase level (P = .044). Kaplan-Meier survival analysis showed that the patients with positive p-Akt expression showed substantially poorer overall survival (p-Akt+ vs p-Akt- 25.3 months [95% confidence interval(CI), 14.4–36.2 months] vs 192.6 months [95% CI, 131.3–253.9 months], P < .001) and progression-free survival (p-Akt+ vs p-Akt- 13.6 months[95% CI, 14.4–36.2 months] vs 134.5 months [95% CI, 131.3–253.9 months], P < .001), respectively. Multivariate Cox regression analysis revealed that patients with DLBCL with p-Akt positivity showed poorer overall survival with 3.2 fold (95% CI, 1.6–6.8, P = .002) risk for death compared to patients with DLBCL with p-Akt negativity. Conclusion Positive expression of p-Akt in DLBCL patients is associated with poorer overall and progression-free survival. Expression of p-Akt may act as an independent poor prognostic factor and might be a novel therapeutic target for DLBCL. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

PF716 CLINICAL IMPACT OF PROGNOSTIC NUTRITIONAL INDEX IN DIFFUSE LARGE B CELL LYMPHOMA

HemaSphere ◽

10.1097/01.hs9.0000561148.15666.da ◽

2019 ◽

Vol 3 (S1) ◽

pp. 313

Author(s):

S.-I. Go ◽

G.-W. Lee

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Prognostic Nutritional Index ◽

B Cell Lymphoma ◽

Clinical Impact ◽

Large B Cell Lymphoma ◽

Nutritional Index ◽

Large B Cell

Download Full-text

Abstract 3533: Clinical impact of NF-KB activation in diffuse large B cell lymphoma.

10.1158/1538-7445.am2013-3533 ◽

2013 ◽

Author(s):

Lina Odqvist ◽

Santiago Montes-Moreno ◽

Margarita Sánchez-Beato ◽

Lydia Sánchez-Verde ◽

Manuela Mollejo ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Clinical Impact ◽

Large B Cell Lymphoma ◽

Large B Cell

Download Full-text

Bone Marow (BM) Involvement in Diffuse Large B Cell Lymphoma (DLBCL): Clinical Impact of Discordant Disease.

Blood ◽

10.1182/blood.v108.11.2031.2031 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2031-2031

Author(s):

Mukesh Chhanabhai ◽

Joseph Connors ◽

Wayne Seville ◽

Dan Matso ◽

Randy Gascoyne

Keyword(s):

Bone Marrow ◽

B Cell ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Clinical Impact ◽

Low Grade ◽

Large B Cell Lymphoma ◽

Clinical Records ◽

Large B Cell

Abstract Background and Methods: Most published studies have suggested that survival of de novo DLBCL with discordant BM involvement by small B cell lymphoma is indistinguishable from patients having a negative staging BM. The aim of the study was to investigate the incidence and clinical impact of BM involvement by concordant and discordant B cell lymphoma in patients with DLBCL seen in a single institution over a 5 year period (1\1\2000 – 31\12\2004). The cases were identified from pathology records and BCCA Lymphoid Cancer Database. Results: The group of interest for this study comprised 652 patients with de novo DLBCL with staging marrow available for review. 60 of 652 (9.2%) of patients with DLBCL had concordant large B-cell lymphoma in their bone marrow. 523 (80.2%) were negative, 16 patients showed what we considered to be atypical lymphoid (ALH) infiltrates lacking definitive features of malignancy. In 50 patients (7.7%) the bone marrow showed discordant histology with predominantly small B-cells, some showing paratrabecular localization. In total there were five cases of TCRBCL in the study, three with marrow involvement. Furthermore, all 54 cases of primary mediastinal B-cell lymphoma (PMBCL) had a negative BM. Of the 652 cases with DLBCL with staging bone marrows available, merging the pathology and clinical databases resulted in 599 patients with complete clinical records. Of these, bone marrows were either not done or deemed inadequate in 101 cases. Therefore, there were 488 patients with DLBCL with an interpretable marrow of which 344 had advanced stage disease. Staging marrows in these patients were negative = 264, positive 41, discordant 28, and ALH 11. The overall survival and progression free survival were strongly affected by the IPI score for these 344 cases (P<0.00001) (see figure). Compared to those without BM involvement patients with concordant large B-cell lymphoma in their BM (n=41) had the worst outcome and those with discordant small B-cell lymphoma in the bone marrow (n=28) had an inferior but intermediate outcome (median survivals (months) = not reached;12 and 20, respectively). Conclusion: Diffuse large B-cell lymphoma is a heterogenous group of lymphomas as demonstrated by gene expression profiling. Our data suggests that discordant low grade B-cell lymphoma in patients who have coincident DLBCL has a poorer prognosis and the presence or absence of BM disease has clinical significance. Though we had very few cases, TCRBCL show a higher incidence of BM involvement in keeping with the reported literature. The absence of marrow disease in PMBCL is consistent with recent data indicating it is a biologically distinct form of DLBCL. Figure Figure

Download Full-text