No abstract

Recent progress in anti-tumor immunotherapy has focused on the significance of the tumor microenvironment in tumor progression and resistance to chemo/radio-therapy. Myeloid cells such as macrophages are predominant stromal components in hematological malignancies. In the present study, we investigated the regulation of programmed death-1 (PD-1) ligand expression in primary central nervous system lymphoma (PCNSL) using PCNSL cell lines and human monocyte-derived macrophages. TK PCNSL cell line-derived soluble factors induced overexpression of PD-1 ligands, indoleamine 2,3-dioxygenase (IDO1), and several other cytokines in macrophages. The expression of PD-1 ligands was dependent on the activation of signal transducer and activator of transcription 3. PD-L1 and IDO1 were overexpressed by macrophage/microglia in PCNSL tissues, and gene expression profiling indicated that IDO1 expression was positively correlated with the expression of macrophage and lymphocyte markers. Macrophage-derived factors did not influence the proliferation or chemo-sensitivity of cell lines. These data suggest that the expression of immunosuppressive molecules, including PD-1 ligands and IDO1, by macrophage/microglia may be involved in immune evasion of lymphoma cells.

Recent findings indicate CD169‐positive lymph node sinus macrophages (LySMs) in the regional lymph nodes (RLNs) play an important role in anti‐cancer immunity. In the present study, we investigated the correlation between CD169 expression in RLNs and clinicopathologic factors. Higher CD169 expression in LySMs was significantly associated with longer cancer‐specific survival (CSS). The density of tumor‐infiltrating lymphocytes (TILs) in the cancer nest and CD169 expression on LySMs were positively associated in patients who underwent pretreatment. As CD169 expression is thought to reflect a high interferon signature in RLNs, we tried to identify immunity‐related genes that are up‐regulated by interferon in macrophages as well as CD169. Indoleamine 2,3‐dioxygenase (IDO1) was found to be elevated by interferon, and expression of IDO1 was tested using immunohistochemistry. IDO1 expression on LySMs was positively correlated with CD169 expression; however, there was no significant correlation between IDO1 and clinicopathologic factors. These results suggest that high expression of CD169 in LySMs reflects a high potential for anti‐cancer immune responses in esophageal cancer patients and that monitoring CD169 expression would be useful for evaluating the potential of anti‐cancer immune reactions.

Adult T-cell leukemia/lymphoma (ATLL) is endemic in southwestern Japan, the Caribbean basin, and parts of central Africa, and is considered to be caused by long-term infection with human T-cell leukemia virus type I. CD204 is a scavenger receptor that is overexpressed on alternatively activated macrophages and is known to be overexpressed in tumor-associated macrophages (TAMs). CD206 is also considered a marker of alternatively activated macrophages. However, no studies have investigated CD206 and TAMs. In the present study, we investigated the significance of CD204(+) and CD206(+) TAMs in ATLL tissue samples. We also investigated the correlations with the Ki-67 labeling index (Ki-67LI) and the number of CD31(+) vessels. We found that the number and ratio of CD204(+) TAMs were closely associated with the Ki-67LI, which reflects lymphoma cell proliferation. The number of CD31(+) vessels was not correlated with the number or ratio of CD204(+) and CD206(+) TAMs. The number and ratio of CD204(+) and CD206(+) TAMs, number of CD31(+) vessels, and the Ki-67LI were not associated with the clinical outcome of patients with ATLL. Although further studies are necessary to uncover the detailed mechanisms of CD204 and lymphoma proliferation, these data may provide novel insight into the pathogenesis of ATLL.

The c-fms proto-oncogene is also known as macrophage colony stimulating factor receptor (M-CSFR) or colony-stimulating factor-1 receptor (CSF-1R), and is expressed on several types of malignant tumor cells and myeloid cells. In the present study, we found that overexpression of M-CSFR was present in adult T-cell leukemia/lymphoma (ATLL) cases. M-CSFR signaling was associated with lymphoma cell proliferation, and M-CSFR inhibition induced apoptosis in lymphoma cells. The ATLL cell line ATL-T expressed M-CSF/CSF-1 and interleukin (IL)-34, which are both M-CSFR ligands. M-CSF and IL-34 expression was seen in ATLL cases, and co-expression of these ligands was detected in 11 of 13 ATLL cases. M-CSFR inhibition suppressed programmed death-1 and -2 ligand in ATL-T cells and macrophages stimulated with conditioned medium from ATL-T cells. Thus, an M-CSFR inhibitor may be useful as additional therapy against ATLL due to direct and indirect mechanisms.