Increased programmed death-1+tumor-infiltrating lymphocytes in classical Hodgkin lymphoma substantiate reduced overall survival

Institute of Pathology, University of Basel, Basel, Switzerland.
Human pathology (Impact Factor: 2.77). 09/2009; 40(12):1715-22. DOI: 10.1016/j.humpath.2009.03.025
Source: PubMed


Programmed death-1 (PD-1), a protein that is physiologically expressed by germinal center-associated helper T cells, has an inhibitory function on T-cell activity. The distribution of PD-1+ lymphocytes in the microenvironment of Hodgkin lymphoma is not random and can serve as a diagnostic marker. We measured the number of PD-1+ lymphocytes in Hodgkin lymphoma and correlated it with the remaining background lymphocyte populations and known biological and clinical key data on a tissue microarray platform encompassing 280 cases of classical Hodgkin lymphoma and 3 cases of nodular lymphocyte-predominant Hodgkin lymphoma. Prognostic cutoff scores were determined by receiver operating curve analysis. The number of PD-1+ tumor-infiltrating lymphocytes in 189 evaluable cases was median of 27 and mean of 269 cells/mm(2), being higher in lymphocyte-rich classical Hodgkin lymphoma and lower in the mixed cellularity variant. Rimming of tumor cells by PD-1+ cells was observed in all cases of nodular lymphocyte-predominant Hodgkin lymphoma but only in 1% of classical Hodgkin lymphomas, particularly in lymphocyte-rich and -mixed cellularity variants. Thus, the presence of PD-1+ rosettes around neoplastic cells is typical but not exclusive for nodular lymphocyte-predominant Hodgkin lymphoma because it may be encountered in classical Hodgkin lymphoma. The PD-1+ cell amount was lower in classical Hodgkin lymphoma cases with 9p24 gains (PD-1 ligand 2 locus) and in cases with higher numbers of FOXP3+ regulatory T cells. An increased amount of PD-1+ tumor-infiltrating lymphocytes above the prognostic cutoff score (23 cells/mm(2)) was a stage-independent negative prognostic factor of overall survival as opposed to the number of FOXP3+ regulatory T cells. Along with the latter, PD-1+ cells might represent important lymphoma/host microenvironment modulators.

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    • "ALCL PD-L1 Tumor cells [28] AML PD-1 Tumor cells [31] ATL, HTLV-1 mediated PD-1, PD-L1 Tumor cells [30] CLL/SLL PD-1 Tumor cells [35] DLCBL PD-1 Tumor cells; TMI [34] [35] FL PD-1 Tumor cells; TMI [33] [35] HL Classical PD-1 TMI [36] NLPHL PD-1 TMI [29] PCM PD-L1 Tumor cells [27] PMBCL PD-L2 Tumor cells [32] "
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    ABSTRACT: Immunotherapy remains an important tool for treatment of hematologic malignancies. The Programmed Death-1 (PD-1) immune checkpoint pathway has emerged as a mechanism of tumor evasion from the anti-tumor immune response. The recent development of anti-PD-1 monoclonal antibodies has offered a targeted approach to cancer therapy. Several agents are in various stages of development and have shown clinical responses across a broad spectrum of both solid and hematologic malignancies. The use of anti-PD-1 therapy in hematologic malignancies is limited but has demonstrated clinical responses in relapsed/refractory disease following multiple lines of therapy. PD-1 blockade may reduce relapse rates for patients who fail to obtain a complete remission prior to autologous hematopoietic cell transplant. The role of the PD-1 pathway for tumor escape is reviewed. We explore the use of anti-PD-1 therapy in hematologic malignancies. The proposed mechanism of PD-1 blockade as a modulator of the innate and acquired immune response is considered. Finally, the challenges of anti-PD-1 therapy and the future direction of investigation in this area are reviewed.
    Blood Reviews 09/2014; 29(1). DOI:10.1016/j.blre.2014.09.004 · 5.57 Impact Factor
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    • "; (ii) expression of the Fas-Ligand (CD95L) [45]; (iii) downregulation of HLA class I antigens; (iv) expression of HLA-G antigens, which play an important role in the inhibition of the NK-cell response [47]; (v) expression of PD-1 (programmed death 1) protein, a negative regulator on the immune response of T cells and (by it's ligand) on HRS cells [48]. Such phenomenons were found to have a negative impact on survival [48] [49]. Also, Steidl et al. showed a strong association of increased numbers of tumorassociated macrophages (CD68 + ) with shortened survival in patients with classic HL [50]. "
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    ABSTRACT: Despite the favorable prognosis of most patients with Hodgkin's Lymphoma (HL), 15-20% of patients remain refractory to chemoradiotherapy, and 20-40% experience relapses following autologous stem cell transplantation (SCT) being used as salvage approach in this situation. Long-term survival of only 20% was reported for patients who failed this option. As some authors suggested the presence of a graft versus HL effect, allogeneic SCT was introduced as a further option. Myeloablative strategies were reported to be able to achieve cure in some younger patients, but high nonrelapse mortality remains a problem. Reduced intensity conditioning, in turn, was found to be associated with high posttransplant relapse rates. As there is currently no standard in the management of HL patients who failed autologous SCT, we here review the literature on allogeneic stem cell transplantation in HL patients with a special focus on the outcomes and risk factors being reported in the largest studies.
    Advances in Hematology 01/2011; 2011:974658. DOI:10.1155/2011/974658
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    • "We also showed a varying distribution of PD-1-positive cells in defined lymphadenopathies, which could indicate a functional relevance of these cells in such instances as well [22]. Analysis of PD-1-positive tumor-infiltrating lymphocytes is diagnostically helpful in nodular lymphocyte-predominant Hodgkin lymphoma (rosetting of PD-1-positive tumorinfiltrating lymphocytes around neoplastic cells) and might also be diagnostically important in classical Hodgkin lymphoma and in T-cell rich large B-cell lymphoma [5] [10] [23]. On average, we found two out of 58 (3%) PD-1-positive SLL/CLL cases on our TMA as well as no PD-1 expression on tumor cells of mantle cell lymphomas, which was verified for SLL/CLL on eight additional newly diagnosed routine cases, stained for PD-1 on conventional full tissue sections. "
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    ABSTRACT: Programmed death-1 (PD-1) is expressed by germinal center-associated helper T-cells and acts as a negative regulator of the immune system. PD-1 is encountered on tumor cells of angioimmunoblastic T-cell lymphoma and is a postulated diagnostic marker in chronic lymphocytic leukemia (CLL/SLL). Recent data suggest prognostic importance of PD-1 in follicular lymphoma (FL). We assessed the diagnostic potential and the prognostic importance of PD-1 in B-cell lymphomas. Distribution of PD-1+ lymphocytes in B-cell lymphomas was studied on 403 cases. Correlation with known biologic and clinical key data was performed. Prognostic cut-off scores were determined by receiver operating curve analysis. PD-1+ tumor-infiltrating lymphocytes were numerous in extranodal marginal zone lymphomas and FL. Their amount decreased from FL grade 1 to grade 3 and to FL with transformation to diffuse large B-cell lymphoma. An increased amount of PD-1 tumor-infiltrating lymphocytes above the prognostic cut-off score (> 2.8%) was a positive prognostic factor of disease-specific survival (DSS) in FL-patients. Five percent of the studied 66 CLL/SLL cases showed unequivocal PD-1 positivity of neoplastic cells. Increased number of PD-1+ tumor-infiltrating lymphocytes is associated with significantly improved DSS in FL and may be useful to predict its heterogeneous clinical behavior. PD-1 has probably limited diagnostic value for primary histopathological CLL/SLL diagnostics.
    Disease markers 09/2010; 29(1):47-53. DOI:10.3233/DMA-2010-0725 · 1.56 Impact Factor
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