Expression of CD38 on Macrophages Predicts Improved Prognosis in Hepatocellular Carcinoma

Abstract

Background: CD38 is involved in the adenosine pathway, which represents one of the immunosuppressive mechanisms in cancer. CD38 is broadly expressed across immune cell subsets, including human macrophages differentiated in vitro from monocytes, but expression by tissue-resident macrophages remains to be demonstrated.Methods: Tissue samples were obtained from 66 patients with hepatocellular carcinoma (HCC) from Singapore and analyzed using immunohistochemistry. Tumor-infiltrating leukocytes (TILs) were further examined using DEPArray™, and the phenotype of freshly isolated TILs was determined using flow cytometry.Results: CD38 was frequently co-expressed with the macrophage-specific marker CD68. CD38+CD68+ macrophage density was associated with improved prognosis after surgery, while total CD68+ macrophage density was associated with poor prognosis. DEPArray™ analysis revealed the presence of large (>10 μm), irregularly shaped CD45+CD14+ cells that resembled macrophages, with concurrent CD38+ expression. Flow cytometry also revealed that majority of CD14+HLA-DR+ cells expressed CD38.Conclusion: CD38 expression was clearly demonstrated on human macrophages in an in vivo setting. The positive association identified between CD38+ macrophage density and prognosis may have implications for routine diagnostic work.

The Roles of CD38 and CD157 in the Solid Tumor Microenvironment and Cancer Immunotherapy

“…In addition, CD38 promotes the activation, proliferation and survival of lymphocytes, as well as the release of pro-inflammatory and regulatory cytokines from dendritic cells and monocytes [10,29]. CD38 is also expressed by monocytes, where it serves as a coreceptor in the MHC Class II-mediated activation of T cells by superantigens [30]. Co-expression of CD38 and human leukocyte antigen-DR isotype (HLA-DR) indicates the presence of recently activated effector CD8+ T cells [20,31,32].…”

“…Coexpression of CD38 and CD68 on macrophages is correlated with improved prognosis after surgical resection by increasing the M1 to M2 macrophage ratio [30] Non-small cell lung cancer…”

“…This is because CD38 suppresses activity of cytotoxic T cells via the adenosinergic pathway [44] -CD38+ macrophages in the TME may promote inflammation and exert anti-tumor effects. This is because CD38 expression is associated with M1 macrophages, which produce pro-inflammatory cytokines [47] -Coexpression of CD38 and CD68 on macrophages is correlated with improved prognosis after surgical resection by increasing the M1 to M2 macrophage ratio [30] Non-small cell lung cancer…”

“…At present, liver resection and transplantation represent the most established treatment methods for early stage HCC, while advanced-stage HCC is treated by chemotherapy with the kinase inhibitor Sorafenib [58]. However, HCC still has a relatively low five-year survival rate and high incidence of recurrence [30]. Cancer -Increases tumor cell proliferation, invasiveness, and dissemination by activating the mTOR pathway [57] -Promotes mesenchymal differentiation [56] by mediating adhesion to extracellular matrix proteins [12] Cells 2020, 9, 26 7 of 18 2.1.…”

“…At present, liver resection and transplantation represent the most established treatment methods for early stage HCC, while advanced-stage HCC is treated by chemotherapy with the kinase inhibitor Sorafenib [58]. However, HCC still has a relatively low five-year survival rate and high incidence of recurrence [30]. Cancer immunotherapy is now being explored as an alternative form of treatment, and studies show promising results.…”