ML-07 High expression of PD-L1 on tumor-associated macrophage is a predictive factor for favorable prognosis in PCNSL

Abstract PD-L1 and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we investigated the expressions of PD-L1 and PD-L2 in surgical specimens from needle biopsies and craniotomies to compare tumor tissue with surrounding tumor tissue (peritumoral tissue) and analyzed the correlation between expression of PD-L1/PD-L2 and survival in patients with PCNSL. We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1- and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. The tumor cells did not express very much PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95%CI: 0–94.6) than intratumoral macrophages (27.5%; 95%CI: 0–81.1, p=0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2-positive peritumoral macrophages (p=0.0429), with very low coefficient correlation (ρ=0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p=0.0008; better MSKCC score, p=0.0103; peritumoral macrophages: low proportion of LDH elevation, p=0.0064) and longer OS (for intratumoral macrophages: high PD-L1=60 months, 95%CI=30–132.6; low PD-L1=24 months, 95%CI=11–48; p=0.032; for peritumoral macrophages: high PD-L1=60 months, 95%CI=30.7-NR; low PD-L1=14 months, 95%CI=3–26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR=0.30, 95%CI=0.12–0.77, p=0.0129). Macrophages in intratumoral and peritumoral tissue expressed PD-L1 and PD-L2 at a higher rate than tumor cells. PD-L1 expression, especially on peritumoral macrophages, seems to be an important prognostic factor in PCNSL.

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PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma

10.21203/rs.2.14925/v3 ◽

2020 ◽

Author(s):

Motomasa Furuse ◽

Hiroko Kuwabara ◽

Naokado Ikeda ◽

Yasuhiko Hattori ◽

Tomotsugu Ichikawa ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Prognostic Significance ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Rank Test ◽

Biological Factors ◽

Peritumoral Tissue

Abstract Background: The prevalence of programmed death-ligand 1 (PD-L1) and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. We also assessed the correlation between biological factors and the prognostic significance of PD-L1 and PD-L2 expression. Methods: We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1- and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. Results: The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95%CI: 0–94.6) than intratumoral macrophages (27.5%; 95%CI: 0–81.1, p=0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2-positive peritumoral macrophages (p=0.0429), with very low coefficient correlation (ρ=0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p=0.0008; better MSKCC score, p=0.0103; peritumoral macrophages: low proportion of LDH elevation, p=0.0064) and longer OS (for intratumoral macrophages: high PD-L1=60 months, 95%CI=30–132.6; low PD-L1=24 months, 95%CI=11–48; p=0.032; for peritumoral macrophages: high PD-L1=60 months, 95%CI=30.7–NR; low PD-L1=14 months, 95%CI=3–26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR=0.30, 95%CI=0.12–0.77, p=0.0129). Conclusions: Macrophages in intratumoral and peritumoral tissue expressed PD-L1 and PD-L2 at a higher rate than tumor cells. PD-L1 expression, especially on peritumoral macrophages, seems to be an important prognostic factor in PCNSL. Future comprehensive analysis of checkpoint molecules in the tumor microenvironment, including the peritumoral tissue, is warranted.

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PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma

10.21203/rs.2.14925/v2 ◽

2019 ◽

Author(s):

Motomasa Furuse ◽

Hiroko Kuwabara ◽

Naokado Ikeda ◽

Yasuhiko Hattori ◽

Tomotsugu Ichikawa ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Prognostic Significance ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Rank Test ◽

Biological Factors ◽

Peritumoral Tissue

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PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma

10.21203/rs.2.14925/v1 ◽

2019 ◽

Author(s):

Motomasa Furuse ◽

Hiroko Kuwabara ◽

Naokado Ikeda ◽

Yasuhiko Hattori ◽

Tomotsugu Ichikawa ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Tumor Cells ◽

Immune Escape ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Cancer Center ◽

Peritumoral Tissue ◽

The Mean ◽

Expression Score

Abstract Background: The prevalence of PD-L1 and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. Methods: We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. The PD-L1 and PD-L2 expressions were semi-quantitatively assessed in tumor and peritumoral tissue. Results: The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The PD-L1 expression score was significantly higher in peritumoral macrophages (1.81; 95%CI: 1.52–2.10) than intratumoral macrophages (1.45; 95%CI: 1.26–1.65) (p=0.0456). The mean PD-L2 expression score was significantly higher in peritumoral macrophages (2.07; 95%CI: 1.81–2.33) than intratumoral macrophages (1.52; 95%CI: 1.35–1.70) (p=0.0002). The macrophage expressions of PD-L1 and PD-L2 were significantly correlated in both tumor tissue (p=0.0179) and peritumoral tissue (p=0.020). Neither PD-L1 nor PD-L2 expression was correlated between intratumoral and peritumoral macrophages (PD-L1, p=0.9198; PD-L2, p=0.0659). PD-L1 expression on peritumoral macrophages tended to be associated with a poor Memorial Sloan Kettering Cancer Center score (p=0.0553). Conclusions: Macrophages in intratumoral and especially peritumoral tissue expressed high levels of PD-L1 and PD-L2 and may play an important role in the immune escape mechanism in PCNSL.

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High Expression of Cathepsin D in Non-Hodgkin’s Lymphomas Negatively Impacts on Clinical Outcome

Disease Markers ◽

10.1155/2010/465040 ◽

2010 ◽

Vol 28 (3) ◽

pp. 167-183 ◽

Cited By ~ 4

Author(s):

Giuseppina Nicotra ◽

Federica Manfroi ◽

Carlo Follo ◽

Roberta Castino ◽

Nicola Fusco ◽

...

Keyword(s):

Clinical Outcome ◽

Tumor Cells ◽

Survival Probability ◽

Cathepsin D ◽

Rank Test ◽

Lysosomal Protease ◽

T Cell Lymphomas ◽

Kaplan Meier ◽

Punctate Pattern ◽

Hodgkin's Lymphomas

The lysosomal protease Cathepsin D (CD) has been implicated in the homeostasis of lymphatic tissues. We investigated whether the level of CD expression influences the progression and the clinical outcome in Non-Hodgkin’s Lymphomas (NHLs). The expression of CD was assessed by immunohistochemistry and immunofluorescence in biopsies of Diffuse Large B Cell Lymphomas (DLBCL, 35 cases), Follicular Lymphomas (FL, 9 cases of grade I-II plus 14 cases of grade IIIB), Chronic Lymphocytic Leukaemias (CLL, 17 cases) and Peripheral T-cell Lymphomas (PTCL, 5 cases). CD staining showed a cytoplasmic punctate pattern compatible with its lysosomal localization. Based on the level of CD expression and the proportion of positive cells, lymphomas were classified as ‘low expressing’ (< 20% of tumor cells) or ‘highly expressing’ (≥ 20% of tumor cells). Lymphomas highly expressing CD were associated with a worse stage (III-IV) at diagnosis (31/34 cases;p= 0.002) and with a poor clinical outcome (i.e., partial remission and death; 28/34 cases;p= 0.03). In the subgroup of aggressive/high grade of malignancy lymphomas (i.e., DLBCL, FL IIIB and PTCL), the Kaplan-Meier curve revealed a very low cumulative overall survival probability (~20% at 5 year) for patients bearing a NHL with > 40% CD-positive cells compared to that of patients bearing a NHL with < 20% CD-positive cells (~70% at 5 year). This correlation was statistically significant (log-rank test,p= 0.01). In Cox multivariate analysis CD failed to be a prognosticator independent of pathologic stage, though the hazard ratio confirmed the association of low expression with a better survival probability. These data indicate that the presence of a high percentage of CD-positive tumor cells negatively reflects on the progression of NHLs.

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NCOG-02. PROGNOSTIC VALIDATION OF THE EANO ESMO CLASSIFICATION OF LEPTOMENINGEAL METASTASIS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.541 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii129-ii129

Author(s):

Emilie Le Rhun ◽

Patrick Devos ◽

Johannes Weller ◽

Katharina Seystahl ◽

Francesca Mo ◽

...

Keyword(s):

Tumor Cells ◽

Leptomeningeal Metastasis ◽

Rank Test ◽

Type I ◽

Type Ii ◽

Primary Tumors ◽

Kaplan Meier ◽

Negative Prognostic Factor ◽

Choice Of Treatment

Abstract BACKGROUND The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) based on clinical (typical/atypical), cytological (positive/negative/equivocal) and MRI (A linear, B nodular, C linear and nodular, D normal or hydrocephalus only) presentation. Type I LM is defined by the presence of tumor cells in the cerebrospinal fluid (CSF) (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the clinical utility of these EANO ESMO LM subtypes for choice of treatment and outcome. PATIENTS AND METHODS We retrospectively assembled data from 254 patients with newly diagnosed LM from different solid tumors, including as main primary tumors breast cancer (n=98, 45%), lung cancer (n=65, 25.5%) and melanoma (n=51, 13.5%). Survival curves were estimated using the Kaplan-Meier method and compared by Log-rank test. RESULTS Median age at LM diagnosis was 56.5 years (range 20-82 years). Typical clinical LM symptoms or signs were noted in 225 patients (88.5%); only 13 patients (5%) were clinically asymptomatic. The most common MRI subtype was A seen in 117 patients (46%). Types B (n=33, 13%), C (n=54, 21%) and D (n=50, 19.5%) were less common. Tumor cells in the CSF were observed in 186 patients (73%) whereas the CSF was equivocal in 24 (9.5%) and negative in 44 (17.5%) patients. Patients with confirmed LM had inferior outcome than patients with probable or possible LM (p=0.0063). Type I patients had inferior outcome than type II patients (p=0.0019). Nodular disease was a negative prognostic factor in type II LM, but not in type I LM (p=0.0138). CONCLUSION The EANO ESMO LM subtypes are highly prognostic and should be considered for stratification and overall design of clinical trials.

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41. PROGNOSTIC VALIDATION OF THE EANO ESMO CLASSIFICATION OF LEPTOMENINGEAL METASTASIS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa073.029 ◽

2020 ◽

Vol 2 (Supplement_2) ◽

pp. ii7-ii8

Author(s):

Emilie Le Rhun ◽

Patrick Devos ◽

Johannes Weller ◽

Katharina Seystahl ◽

Francesca Mo ◽

...

Keyword(s):

Tumor Cells ◽

Leptomeningeal Metastasis ◽

Rank Test ◽

Type I ◽

Type Ii ◽

Primary Tumors ◽

Log Rank Test ◽

Kaplan Meier ◽

Negative Prognostic Factor

Abstract BACKGROUND The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) based on clinical (typical/atypical), cytological (positive/negative/equivocal) and MRI (A linear, B nodular, C linear and nodular, D normal or hydrocephalus only) presentation. Type I LM is defined by the presence of tumor cells in the cerebrospinal fluid (CSF) (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the clinical utility of these EANO ESMO LM subtypes. PATIENTS AND METHODS We retrospectively assembled data from 254 patients with newly diagnosed LM from different solid tumors, including as main primary tumors breast cancer (n=98, 45%), lung cancer (n=65, 25.5%) and melanoma (n=51, 13.5%). Survival curves were estimated using the Kaplan-Meier method and compared by Log-rank test. RESULTS Median age at LM diagnosis was 56.5 years (range 20–82 years). Typical clinical LM symptoms or signs were noted in 225 patients (88.5%); only 13 patients (5%) were clinically asymptomatic. The most common MRI subtype was A seen in 117 patients (46%). Types B (n=33, 13%), C (n=54, 21%) and D (n=50, 19.5%) were less common. Tumor cells were observed in the CSF in 186 patients (73%) whereas the CSF was equivocal in 24 (9.5%) and negative in 44 (17.5%) patients. Patients with confirmed LM had inferior outcome than patients with probable or possible LM (p=0.0063). Type I patients had inferior outcome than type II patients (p=0.0019). Nodular disease was a negative prognostic factor in type II LM, but not in type I LM (p=0.0138). CONCLUSION The presence of tumor cells in the CSF appears to have a greater prognostic role than the neuroimaging presentation. EANO ESMO LM subtypes are highly prognostic and should be considered in the design of clinical trials.

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Arginine methylation of EGFR in circulating tumor cells: A new biomarker for predicting resistance to anti-EGFR agents.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3590 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3590-3590

Author(s):

Krittiya Korphaisarn ◽

Chao-Kai Chou ◽

Weiya Xia ◽

Callisia Clarke ◽

Jennifer S Davis ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Arginine Methylation ◽

Rank Test ◽

Positive Staining ◽

Egfr Ligands ◽

Kaplan Meier

3590 Background: Arginine methylation of the epidermal growth factor receptor (meEGFR) increases binding affinity of EGF and other EGFR ligands, reduces the efficacy of anti-EGFR agents in vivo, and is reported to have a role in predicting response to anti-EGFR agents. This study aimed to investigate the predictive impact of meEGFR in metastatic colorectal cancer (mCRC) patients (pts) treated with anti-EGFR agents using blood-based testing. Methods: 15 mL of blood were collected from mCRC pts with documented disease progression following anti-EGFR treatment (Rx). Circulating tumor cells (CTCs) were isolated using antibody (ab)-independent micro-fluidic cassette-based technology (Parsortix system), which separates CTCs on the basis of size and deformability. CTCs were identified based on negative staining for CD45ab and positive staining for EpCAMab. meEGFR was identified based on positive staining for me-R198/200ab on CTCs. Associations between meEGFR-CTCs and total CTCs with progression free survival (PFS) were determined by Kaplan-Meier method and compared by the log-rank test. Results: A total of 47 mCRC pts were prospectively included in this study. CTCs were identified in 30 out of 47 cases (64%). Of those 30, meEGFR-CTCs were identified in 19 cases (63%). Mean total CTCs and meEGFR-CTCs counts were 3.6 (range 0-52) and 2.3 (range 0-30) cells per 7.5ml, respectively. There was no association between meEGFR-CTCs and clinic-pathological features (age, sex, tumor site & grade), line of anti-EGFR Rx, previous irinotecan used, or NRAS, BRAF, PIK3CA, and MSI status. However, in RASwt/BRAFwtmCRC pts, high levels of meEGFR ratio (defined as > 0.25 meEGFR-CTCs per total CTCs) was associated with significantly inferior PFS with anti-EGFR Rx (median PFS 5.4 mo vs. 8 mo, HR 3.4, 95% CI of 1.5-7.9, P = 0.004). By contrast, high levels of total CTCs ( > 3 cells/per 7.5 ml) had no impact on PFS with anti-EGFR Rx. Conclusions: We have successfully isolated CTCs from mCRC pts’ blood using Parsortix system. Elevated levels of arginine methylated EGFR is associated with a shorter PFS with anti-EGFR-based Rx. Assessment of meEGFR-CTCs may provide a “liquid biopsy” biomarker for reduced efficacy from anti-EGFR Rx.

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Therapeutic Targeting of Lymphoma-Associated Vascular Pericytes,

Blood ◽

10.1182/blood.v118.21.3725.3725 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3725-3725

Author(s):

Jia Ruan ◽

Leandro Cerchietti ◽

Chunjie Wang ◽

Lei Fan ◽

Shao Ning Yang ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Cells ◽

Tumor Tissue ◽

B Cell Lymphoma ◽

Therapeutic Effects ◽

Imatinib Treatment ◽

Xenograft Tumor ◽

Antibody Treatment ◽

Inhibition Of Proliferation ◽

Human Lymphoma

Abstract Abstract 3725 Growing evidence has implicated the tumor microenvironment, demarcated by neo-vessels, as an essential disease compartment which influences neoplastic growth and clinical outcome in human lymphoma. The mechanisms whereby stromal cells contribute to the pathogenesis and progression of lymphoma remain poorly understood. Pericytes / vascular smooth muscle cells (VSMC), regulated by platelet-derived growth factor receptor β (PDGFRβ) signaling, play important roles in endothelial cell survival and vascular stability. We hypothesized that the functionality and stability of an effective lymphoma-associated vascular network depends upon the integrity of vascular pericytes, and that biologic agents which selectively target vascular pericytes would induce endothelial dysfunction and impair lymphoma growth. We tested our hypothesis in SCID mice bearing human diffuse large B-cell lymphoma (DLBCL) cell lines by treating with selective PDGFRβ inhibitors including imatinib mesylate and monoclonal anti-PDGFRβ antibody. Treatment with imatinib impaired tumor growth of human lymphoma xenografts including Farage, Karpas422 and OCI-Ly7, while the tumor cells themselves neither expressed PDGFRβ nor were inhibited by imatinib directly. Confocal microscopic analysis of the xenograft tumor tissue showed decreased microvessel density, decreased vascular functional flow, as well as increased vascular leak and apoptosis in the imatinib-treated cohorts, compared to untreated controls. Imatinib targeted tumor-associated PDGFRβ+ pericytes in vivo by inducing apoptosis and disruption of the PDGFRβ+ perivascular network, and PDGFRβ+ VSMC in vitro by inhibition of proliferation. FACS analysis of mononuclear cell suspensions of xenograft tumor tissue revealed decreased numbers of mature pericytes and endothelia, as well as their progenitors, with imatinib treatment. Compared to imatinib, treatment with anti-PDGFRβ monoclonal antibody partially inhibited the growth of Farage lymphomas by depleting pericytes and attenuating angiogenesis. Lastly, microarray analysis of differentially expressed genes in PDGFRβ+ VSMC treated with imatinib showed significant down-regulation of genes implicated in proliferation, survival and angiogenesis, including those within the PI3K/AKT and MAPK/ERK1/2 pathways downstream of PDGFRβ signaling. Taken together, these data suggest that effective targeting of angiogenesis within the tumor microenvironment, without directly targeting tumor cells, can translate into therapeutic effects in DLBCL lymphoma models. PDGFRβ+ pericytes may represent a novel, non-endothelial, anti-angiogenic target for lymphoma therapy. Disclosures: Leonard: glaxosmithkline: Consultancy; EMD Serono: Consultancy; Sanofi Aventis: Consultancy; Pfizer: Consultancy; Immunomedics: Honoraria; Cell Therapeutics: Consultancy; Celgene: Consultancy; Johnson and Johnson: Consultancy; Calistoga: Consultancy; Cephalon: Consultancy; Biogen IDEC: Consultancy; Hospira: Consultancy; Millenium: Consultancy; Novartis: Consultancy; Abbott: Consultancy; Seattle Genetics: Consultancy.

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CD38 Protects Tumor Cells from NK Lysis

Blood ◽

10.1182/blood.v126.23.5389.5389 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5389-5389

Author(s):

Anlai Wang ◽

Guang Yang ◽

Zhili L Song ◽

Francisco J Adrian

Keyword(s):

Nk Cells ◽

Tumor Cells ◽

Cell Lines ◽

B Cell Lymphoma ◽

Cell Lysis ◽

Protective Role ◽

Target Cells ◽

Median Percentage ◽

Protective Function ◽

Cd38 Expression

Abstract Expression of the type II glycoprotein CD38 in hematological malignancies is abnormally high compared to that in normal cells of hematopoietic origin. Across all malignancies, the highest CD38 expression levels are detected on the surface of multiple myeloma (MM) cells. The high CD38 level has prompted the development of anti-CD38 antibody-based therapies, like daratumumab and isatuximab (SAR650984), that are promising therapeutics for the treatment of patients with MM. Cellular functions associated with CD38 include co-receptor mediated signaling, cell adhesion and ecto-enzymatic conversion of NAD to modulate calcium signaling and adenosine synthesis; but other than allowing antibody-mediated engagement of innate immunity, the role of CD38 in MM is not fully understood. In order to investigate a potential immune-protective role for CD38, we evaluated a panel of 15MM and 6 diffuse large B-cell lymphoma (DLBCL) cell lines with varying levels of CD38 for their susceptibility to NK-mediated lysis. Briefly, calcein AM pulsed target cells were incubated with NK-92.CD16 NK cells (E:T=3:1) for 1 hr and cell lysis measured as a function of the fluorescent calcein released into the supernatant. In an initial experiment, we observed that the percentage of cell lysis for all lines with >100,000 CD38s per cell was low, below 10%. The cell lines with <100,000 CD38s per cell were more susceptible to NKs, with a median percentage cell lysis of around 25%. The observed levels of cell lysis were not correlated with the levels of released IFNγ or TNFα. The differential lytic activity against the target cells led to the hypothesis that CD38 might have a role in protecting the tumor cells from NK-mediated lysis. To investigate this, we first knocked down CD38 in SUDHL-8 cells using shRNA, decreasing the levels of CD38 from 246,000 to 51,000 per cell. This resulted in an increase in the percentage of lysed cells from 25% to more than 50%, likely reflecting a loss of protection against the NK cells. We next overexpressed CD38 in U266 cells, increasing the CD38 levels from 9,000 to 327,000 per cell. As a result, the percentage of lysis decreased from more than 60% to around 30%, indicating that U266 cells are now more resistant to the lysis by NK cells. The protection that CD38 seems to confer to CD38-overexpressing U266 cells is completely lost by addition of isatuximab which triggers CD16-mediated lysis (antibody dependent cellular toxicity, ADCC). Whether the protective function of CD38 described here is a direct or an indirect protection mechanism is currently under investigation. Disclosures Off Label Use: isatuximab (SAR650984, anti-CD38 antibody). Song:Sanofi: Employment. Adrian:Sanofi: Employment.

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Outcome in different molecular subtypes of diffuse large B-cell lymphoma: Indian experience.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18518 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18518-e18518

Author(s):

Gaurav Prakash ◽

Atul Sharma ◽

Vinod Raina ◽

Lalit Kumar ◽

Mehar C Sharma

Keyword(s):

B Cell ◽

Molecular Subtypes ◽

Remission Rate ◽

Prognostic Score ◽

Performance Status ◽

B Cell Lymphoma ◽

Rank Test ◽

Kaplan Meier ◽

Number Of Patients ◽

Paraffin Block

e18518 Background: DLBCL has emerged as a heterogeneous disease and gene expression profiling has divided it into distinct molecular subtypes of Germinal center B-Cell (GCB) and Non-GCB- cell origin. These subtypes are reported to vary in the treatment responses and outcome. Methods: We analysed 97 consecutive patients of DLBCL who had satisfactory paraffin block of baseline biopsy. After reviewing diagnosis of DLBCL, sequential immunohistochemical staining with CD10, bcl6 and MUM1 was performed in all the cases. Using these markers the cases were sub-classified into GCB and non-GCB types as per Hans’ algorithm. Baseline presentation, stage, international prognostic score and treatment outcome were recorded. Survival was assessed by Kaplan-Meier survival curves and results were compared using log-rank test. Results: Thirty-three (34%) patients were classified in GCB group while 64(66%) patients in non-GCB group. Median age in both the groups was 50 years. High IPI score2-5 (GCB-34%, non GCB-72%;p 0.005) and stage 3,4 (GCB-39%,nonGCB-61%;p 0.04) were higher in non-GCB group. All the patients were treated with 6-8 cycles of CHOP based regimen and involved field radiotherapy wherever required. Complete remission rate (GCB-52%, nonGCB-27%; p0.02) was higher in GCB group. Three year overall survival, 75% and 63 %( p0.04), and event free survival was 63% and 43 %( p0.02) in GCB and non GCB subtypes, respectively. There was no difference in between two groups for performance status, LDH level and age. Conclusions: In our study, GCB-DLBCL patients had better response rate, EFS and OS in comparison to non GCB subtype. There were higher number of patients with advanced stage and high IPI score in non-GCB subtype which might have contributed to the poorer outcome.

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