Tumor microenvironment composition in pediatric classical Hodgkin lymphoma is modulated by age and Epstein‐Barr virus infection

Abstract

Classical Hodgkin lymphoma (cHL) is characterized by a small number of neoplastic cells in a background of reactive cells. Children and adults differ in constitution and functionality of the immune system and it is possible that there may be agerelated differences in tumor microenvironment composition in cHL. One hundred children with pediatric cHL were studied. Tumor-infiltrating lymphocytes were analyzed by immunohistochemistry (IHC) and image analysis. Epstein-Barr virus (EBV) status was determined by EBER-specific in situ hybridization and IHC. Results were analyzed in the context of age-group, histological characteristics and clinical follow-up. EBV-status was not associated with age-group. Children <10 years and EBV1 cases were characterized by a more intense T cell infiltrate, exhibiting a cytotoxic/Th1 profile, characterized by higher numbers of CD31, CD81, TIA11 and TBET1 lymphocytes. Extranodal disease (p 5 0.016) and high number of GranzymeB1 lymphocytes (p 5 0.04) were independently associated with reduced progression-free survival (PFS). Yet, in EBV1 cases, improved outcome was observed in cases with low numbers of FOXP31 lymphocytes (p 5 0.046), FOXP3/CD8 ratio < 1 (p 5 0.021) and TBET/CMAF ratio < 1 (p 5 0.017). By contrast, in EBV2 cases, poor survival was observed in cases with extranodal disease (p 5 0.028), MC subtype (p 5 0.009) and high numbers of TIA11 (p 5 0.044) and GranzymeB1 (p 5 0.04) lymphocytes. The results suggest that in EBV1 cHL an effective immune response directed against viral or tumor antigens may be triggered in the tumor microenvironment and that physiological and age-related changes of the immune system may also modulate the tumor microenvironment in pediatric cHL.Classical Hodgkin lymphoma (cHL) is characterized by a small number of neoplastic, Hodgkin and Reed-Sternberg (HRS) cells, in a background of inflammatory non-neoplastic cells, mainly B and T cells. 1 The clinical and pathological characteristics of cHL are thought to result from an immune dysfunction, characterized by the deregulated expression of several cytokines and chemokines, 2 and an inadequate immune response due to poor immunogenicity of HRS cells, the immunosuppressive effects exerted by the tumor cells and/or the poor response of the host immune system. 2 At a local level, the tumor microenvironment is maintained by a crosstalk between malignant and reactive cells in the microenvironment, mediated by cytokines and chemokines expressed by both, HRS and inflammatory cells. 2 Increasing evidence of the importance of tumor microenvironment in the pathogenesis of and clinical response to cHL has come from immunohistochemical and molecular studies. [2][3][4] Particularly, the number of several intratumoral cell populations, such as cytotoxic and regulatory (Treg) T cells, 2,5,6 or the ratio between these populations 7-9 have been described as being associated with therapeutic response.Up to now, however, all these studies have been conducted in adult patients or a mixture of adolescents and adults. It is poss...

Serum CD163 and TARC as Disease Response Biomarkers in Classical Hodgkin Lymphoma

“…We observed a modest but significant correlation between tissue and sCD163, and also (consistent with previous studies of tissue CD163) that sCD163 correlated with B symptoms and Ann Arbor stage (13,14). Previous studies have implied that EBV þ HRS cells modulate the tumor microenvironment (36)(37)(38). Intriguingly, we show a strong positive correlation with sCD163 and plasma EBV-DNA levels, suggesting a possible interaction with EBV proteins in HRS cells and CD163 þ monocyte/ macrophages.…”

Tumor-Associated Macrophages in Pediatric Classical Hodgkin Lymphoma: Association with Epstein-Barr Virus, Lymphocyte Subsets, and Prognostic Impact

“…The clinical features of these cases have been previously described (2). All patients were treated according to standard pediatric protocols as previously described (2). For 5 cases, there was not sufficient clinical data and these were excluded from the survival analysis.…”

“…We have shown recently that in EpsteinBarr virus (EBV) þ pediatric cHL the tumor microenvironment is characterized by a cytotoxic/T-helper cell 1 (T H 1) profile (2). Furthermore, cases with a small number FOXP3 þ regulatory T cells (Treg) and a FOXP3/CD8 ratio less than 1 in the tumor microenvironment were associated with an improved outcome.…”

“…Furthermore, cases with a small number FOXP3 þ regulatory T cells (Treg) and a FOXP3/CD8 ratio less than 1 in the tumor microenvironment were associated with an improved outcome. We, therefore, hypothesized that in pediatric EBV þ cHL an effective cytotoxic immune response directed against viral or tumor antigens may be triggered in the tumor microenvironment (2)(3). Recent studies have consistently reported that high numbers of tumor-associated macrophages (TAM) are associated with adverse outcome in adult cHL (4)(5)(6).…”

Epstein-Barr virus DNA in serum as an early prognostic marker in children and adolescents with Hodgkin lymphoma

“…[17][18][19] In contrast to baseline, EBV DNA positivity at day 8 after the initiation of chemotherapy was associated with lower 4-year EFS (67% for serum EBV DNA 1 vs 89% for serum EBV DNA 2 patients; P 5 .002; Figure 1B). Because all of the first events in this cohort were relapse or progressive disease, it seems that the presence of EBV DNA in cell-free blood 8 days after the initiation of therapy is associated with treatment failure.…”