Meta-analysis of the prognostic and clinical value of tumor-associated macrophages in adult classical Hodgkin lymphoma

Abstract

BackgroundThe prognostic significance of tumor-associated macrophages (TAM) in adult classical Hodgkin lymphoma (cHL) remains controversial. Here, we report a meta-analysis of the association of CD68 and CD163 infiltration on the clinical outcome of adult cHL.MethodsA comprehensive search to identify relevant articles was performed in PubMed, Embase, and Google Scholar on January 31, 2016. Using the fixed effect or random effects model of DerSimonian and Laird, hazard ratios (HR) or odds ratios (OR) with 95 % confidence intervals (CIs) were used as the effect size estimate.ResultsTwenty-two eligible studies with a total of 2959 patients were identified. Our analysis indicated that a high density of CD68+ TAMs in the tumor microenvironment of adult cHL predicted poor overall survival (OS) (HR: 2.41; 95 % CI, 1.92–3.03), shorter progression-free survival (PFS) (HR: 1.78; 95 % CI, 1.45–2.18), and poor disease-specific survival (HR: 2.71; 95 % CI, 1.38–5.29). High density of CD163+ TAMs in the tumor microenvironment of adult cHL also predicted poor OS (HR: 2.75; 95 % CI, 1.58–4.78) and poor PFS (HR: 1.66; 95 % CI, 1.22–2.27). In addition, we demonstrated that a high density of either CD68+ or CD163+ TAMs was associated with the presence of Epstein-Barr virus in neoplastic cells (ORCD68: 3.13; 95 % CI, 2.02–4.84; ORCD163: 2.88; 95 % CI, 1.55–5.34). A high density of either CD68+ or CD163+ TAMs tend to be associated with a more advanced clinical stage (ORCD68: 1.25; 95 % CI, 0.93–1.67; OR CD163: 1.19; 95 % CI, 0.86–1.63), B-symptoms (ORCD68: 1.35; 95 % CI, 0.90–2.01; ORCD163: 2.19; 95 % CI, 0.96–5.03), higher International Prognostic Factors Project Score (ORCD68: 1.20; 95 % CI, 0.67–2.15; ORCD163: 2.00; 95 % CI, 0.92–4.35), and bulky disease (ORCD68: 1.47; 95 % CI, 0.88–2.47; ORCD163: 1.19; 95 % CI, 0.72–1.96).ConclusionsOur analyses suggest that a high density of either CD68+ or CD163+ TAMs is a robust predictor of adverse outcomes in adult cHL. Increased TAMs should be taken into account to further improve prognostic stratification and the planning of appropriate therapeutic strategies.

Macrophage targeting: opening new possibilities for cancer immunotherapy

“…Most solid tumours include a variety of immune cells such as regulatory T cells, myeloid‐derived suppressor cells and tumour‐associated macrophages (TAM) that can suppress CTL functions . Among these cells, TAM is one of the most abundant cell types in solid tumours and their infiltration into the tumour associates with poor prognosis in most solid tumours . Furthermore, macrophages isolated from mouse and human solid tumours can directly suppress T‐cell responses and NK cell cytotoxicity in vitro .…”

“…6,7 Among these cells, TAM is one of the most abundant cell types in solid tumours 8 and their infiltration into the tumour associates with poor prognosis in most solid tumours. [9][10][11][12][13][14] Furthermore, macrophages isolated from mouse and human solid tumours can directly suppress T-cell responses 15,16 and NK cell cytotoxicity 17,18 in vitro. It is also reported that depletion of TAM enhances CD8 + Tcell-mediated antitumour immunity under treatment with chemotherapy in a mouse model of breast cancer.…”

Histology of pediatric classic Hodgkin lymphoma: From diagnosis to prognostic stratification

“…The latter are calculated by integrating clinical‐radiological parameters, including disease stage and site, the number of affected nodal regions, the presence of bulky disease and B symptoms 4 . Recent studies have also suggested a prognostic role for serologic and molecular markers, such as platelet and white blood cell counts, ferritin and albumin levels, 4‐6 erythrocyte sedimentation rate (ESR), 7 tumor‐associated mutations and polymorphisms, 8,9 and features of the tumor microenvironment 10,11 . None of these markers has entered the clinical practice as yet.…”

“…4 Recent studies have also suggested a prognostic role for serologic and molecular markers, such as platelet and white blood cell counts, ferritin and albumin levels, 4-6 erythrocyte sedimentation rate (ESR), 7 tumor-associated mutations and polymorphisms, 8,9 and features of the tumor microenvironment. 10,11 None of these markers has entered the clinical practice as yet. The prognostic relevance of histology is also a matter of debate.…”

Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells

“…High frequency of CD68+ TAM in HL biopsies has been correlated with poor overall survival. (19–25) Immunosuppressive and pro-tumor macrophages have been defined as M2 type, as opposed to inactivated (M0) or anti-infection/tumor macrophages (M1). (26–28) Thus, HL represents a unique opportunity to study the impact of the TME on immunotherapy.…”