Expression of c-MYC and MMP9 in Alternatively Activated Macrophages (M2) of Classical Hodgkin Lymphoma

Classical Hodgkin Lymphoma (CHL) is a monoclonal lymphoid neoplasm that accounts for approximately 30% of all lymphomas in the United States. Although multiagent chemotherapy and radiation therapy have made CHL a highly curable disease, approximately 15-20% of patients are refractory to the treatment or relapsed after remission. The rich inflammatory cellular microenvironment plays an important role in the pathogenesis of CHL. Gene-expression profiling has identified a gene signature of tumor-associated macrophages (TAMs) that was significantly associated with primary treatment failure. The potential of macrophage-specific markers, CD68 and CD163, as prognostic markers for resistance to therapy in CHL patients has been investigated; however, these studies generated inconsistent results. Roughly TAMs could be characterized into two distinct polarization states; the classically activated type 1 macrophages (M1) associated with acute inflammation and T-cell immunity and the alternatively activated type 2 macrophages (M2) associated with the promotion of the tumor growth. In the present study, we hypothesize that the specific type of TAMs, M2, may predict poor prognosis in CHL. To test this hypothesis, we examined the correlation between expressions of two M2-specific markers, c-MYC and matrix metalloproteinase 9 (MMP-9), with disease recurrence in a total of 42 cases of CHL, mostly nodular sclerosis subtype. Both c-MYC and MMP-9 are good candidate markers because c-MYC has been shown to be a specific M2 marker and plays a central role in M2 differentiation. In addition, matrix metalloproteinase 9 (MMP-9) is a M2 specific marker that directly related to its protumoral function. Immunohistochemical staining showed that both c-MYC and MMP9 are expressed in a subset of macrophages, but not in Hodgkin Reed-Sternberg (HRS) cells. By comparing the percentage of positive stains of these two markers within HRS rich areas in the primary tumor samples, we found that there was no significant difference in either c-MYC or MMP9 staining between patients who later recurred (n=6) or did not recur (n=36). The role of TAMs or an unidentified subtype of TAMs in predicting resistance to therapy in CHL patients remains to be determined.