Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classic Hodgkin lymphoma

Sánchez-Aguilera, Abel; Montalbán, Carlos; Cueva, P. de la; Sánchez-Verde, Lydia; Morente, Manuel; García‐Cosío, Mónica; García-Laraña, José; Bellas, Carmen; Provencio, Mariano; Romagosa, V.; Sevilla, Alberto Fernández de; Menárguez, Javier; Sabı́n, Pilar; Mestre, María J.; Méndez, Miguel; Fresno, Manuel; Nicolás, Concepción; Piris, Miguel Á.; Garcı́a, Juan F.

doi:10.1182/blood-2005-12-5125

Cited by 133 publications

(137 citation statements)

References 50 publications

(53 reference statements)

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“…Moreover, the presence of a high percentage of activated CTLs (granzyme B þ ) in the affected tissue is a marker of unfavorable prognosis associated with shorter progression-free survival. 10,76 These findings suggest that CTLs that potentially target the HRS cells either fail to penetrate the tumor site or fail to function within the tumor microenvironment. This could be the final consequence of changes in the HL cells, such as downregulation of MHC-I in HRS cells, 77 or induction of local T-cell anergy by IL10, TGF-b, expression of perforin-neutralizing proteins and induction of apoptosis in CTLs by HRS cells via CD95L.…”

Section: Hodgkin Lymphomamentioning

confidence: 99%

“…A small number of FOXP3 þ (Treg) cells and a high degree of infiltration of TIA-1 þ cells (CTLs, NK, neutrophils and macrophages) represent an independent prognostic factor of unfavorable outcome (event-free and disease-free survivals). 9 Another interesting observation is the presence of STAT1-activated macrophages surrounding HL cells, associated with unfavorable prognosis, 10 which could be associated with the immunosuppressive capacity of STAT1-activated macrophages 32 (Figure 1b).…”

Section: Hodgkin Lymphomamentioning

confidence: 99%

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Lymphoma microenvironment: culprit or innocent?

2007

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Studies are revealing that lymphoid neoplasms are characterized by well-defined chromosome translocations and by the accumulation of subsequent molecular alterations involving mainly the cell cycle and/or apoptotic pathways. However, survival of B and T tumor cells is also dependent on the interactions with the accompanying cells that comprise the lymphoma microenvironment. Although non-tumor cells can contribute both positive and negative signals to the lymphoma cells, in this review we present compelling evidence of the essential influence of the tumor microenvironment on the initiation and progression of specific lymphoma types, highlighting some new therapeutic approaches that target the lymphoma microenvironment.

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Section: Hodgkin Lymphomamentioning

confidence: 99%

Section: Hodgkin Lymphomamentioning

confidence: 99%

Lymphoma microenvironment: culprit or innocent?

2007

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“…[27] Gene expression profiling studies have evidenced an adverse outcome in patients with the macrophage gene signature. [19,[31][32][33] The most common marker used for immunohistochemical detection of TAMs is CD68, which is expressed in a wide range of monocytes/macrophages and dendritic cells. [23,24] Published by Sciedu Press In the current study, CD68+ TAM infiltration is increased in cHL.…”

Section: Discussionmentioning

confidence: 99%

High tumour-associated macrophages infiltration is correlated with poor survival outcome in classical Hodgkin’s lymphoma

Al-Maghrabi

Gomaa

Al-Mansouri

et al. 2015

JST

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Background: Classical Hodgkin's lymphoma (cHL) represents the majority of HLs with a relatively good prognosis. In 20% of patients, primary treatment fails. Prediction of treatment failure is critical. A gene signature of tumour associated macrophages (TAM) correlated with response to treatment as CD68 positive TAM was found to be associated with shortened survival. We aim to investigate the relation CD68+TAM infiltration to patients' outcome. Patients and Methods: Pathological materials of 115 patients with cHL were used. Clinical characteristics of patients were collected from the records. CD68 immunostaining was performed to determine the number of infiltrating TAM and subsequently followed by stratification of results. Results of CD68 immunostaining were statistically analysed to correlate the extent of CD68+ TAM infiltration with clinicopathological characteristics, treatment outcome, and patients' survival. Results: High CD68+TAM infiltration was observed in more patients of cHL (96/115 of patients = 83.5%). High CD68+TAM infiltration was associated with extranodal presentation (P = .001), and higher stage (P = .022). No associations with other clinicopathological parameters were found. High CD68+TAM infiltration was not found to be an independent predictor of treatment outcome. High CD68+TAM infiltration correlated with disease free survival (DFS) (log-rank = 4.505, P = .034) but not with disease specific survival (DSS) (log-rank = 1.371, P = .242). Conclusions:The results of our study support the adverse prognostic effect of high TAM in cHL. Technical standardisation of CD68 immunostaining is required to establish TAM infiltration as a prognostic predictor. Also in vivo and in vitro cHL models have to be established for proper understanding of the role of CD68 in modulating the TAM in cHL.

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“…This effect is also consistent with lymphoma occurrence. It was previously reported that the genes associated with the tumor microenvironment, cell growth and̸or apoptosis and regulation of mitosis were associated with response to treatment and the outcome of patients with Hodgkin's lymphoma (10). In addition, the tissue inhibitor of metalloproteinase 1 (TIMP-1) was found to promote EBV-related lymphoma growth, and also inhibit tumor angiogenesis.…”

Section: Epstein-barr Virus (Ebv) Is Associated With a Number Of Diffmentioning

confidence: 99%

Enhanced antitumor effect of combining chemotherapy with Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes in mice with EBV-related non-Hodgkin's lymphoma

Deng

Liu

et al. 2015

Molecular and Clinical Oncology

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Abstract. Epstein-Barr virus (EBV)-related non-Hodgkin's lymphoma (NHL) represents a major problem in hematological clinical studies due to its drug tolerance and refractoriness. EBV infection is a key factor driving the process of tumor growth. Immune therapy is an important biotherapeutic method of treating cancer, which is attracting increasing attention. We hypothesized that combining conventional chemotherapy with immune therapy in the treatment of EBV-related NHL may achieve better outcomes. First, we successfully cloned large numbers of EBV-specific T cells by immune stimulation ex vivo. Subsequently, the combined therapy was applied in a murine model of human EBV-related NHL. As expected, combined therapy inhibited tumor growth more effectively compared with monotherapy. In addition, we continuously tested the tumor-associated immune microenvironment and observed that the numbers of tumor-infiltrating cytotoxic T lymphocytes (CTLs) and macrophages were elevated following combined therapy. These effects suggest that EBV-specific CTLs may indirectly promote an innate immune reaction in lymphoma by activating tumor-infiltrating macrophage proliferation. Our findings may provide a guide for the prospective treatment of EBV-related NHL.

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Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classic Hodgkin lymphoma

Cited by 133 publications

References 50 publications

Lymphoma microenvironment: culprit or innocent?

Lymphoma microenvironment: culprit or innocent?

High tumour-associated macrophages infiltration is correlated with poor survival outcome in classical Hodgkin’s lymphoma

Enhanced antitumor effect of combining chemotherapy with Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes in mice with EBV-related non-Hodgkin's lymphoma

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