M2 Macrophage Infiltration Is Closely Associated with Poor Prognosis for Adult T-Cell Leukemia/Lymphoma (ATLL),

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by a retrovirus, human T-cell lymphotropic virus type I, and characterized by an aggressive clinical course and poor prognosis. Although several factors associated with this poor prognosis have been identified, including high-level Ki67 antigen expression and high serum levels of calcium, parathyroid hormone-related protein, soluble interleukin-2 receptor, β2-microglobulin, and neuron-specific enolase, the accuracy of current prognostic models for prediction of the outcome of treatment is inadequate, and clinically relevant biomarkers have not been established. Tumor-associated macrophages, which are known to possess the immunosuppressive M2 macrophage phenotype, contribute to tumor growth, invasion, and metastasis by producing various mediators. Macrophage polarization is divided into types M1 and M2 based on the expression of membrane receptors, cytokines, and chemokines. M1 expresses CD80, interleukin (IL)-6, IL-12, and chemokine receptor 7, while M2 expresses CD163, IL10, and chemokine ligand 22. The classically activated M1 macrophages exhibit antitumor functions and the alternatively activated M2 macrophages protumor functions, which contribute to the development and progression of tumors. CD163 is a monocyte/macrophage-restricted membrane protein belonging to the scavenger receptor cysteine-rich domain family and it functions as an endocytic receptor for a hemoglobin-haptoglobin complex. CD163 expression has been associated with an anti-inflammatory M2 macrophage phenotype and is believed to be useful for distinguishing M2 macrophages from pro-inflammatory M1 macrophages. Macrophages, especially M2 polarized macrophages, preferentially express CD163, but no studies have investigated macrophage phenotypes in ATLL. The aim of our study was therefore to investigate CD163 expression, which has been used as a marker for M2 macrophages, and the relationship between macrophage activation and prognosis for ATLL in order to gain new information about the therapeutic implications of this relationship for ATLL.

Between 1985 and 2003, 75 cases of ATLL were examined. The male-to-female ratio was 1.34:1 and the median age 63 years (range: 35–87 years). Advanced clinical stages were identified in 75% of the patients, and lactic dehydrogenase was elevated in 25%. Most patients were treated with combination chemotherapy and the median survival period was 271 days (range: 4–3, 807 days). We performed a retrospective study on the immunohistochemical expression of macrophage markers (CD68, CD163) and their correlation with overall survival for the 75 ATLL patients. Paraffin sections were examined immunohistochemically by using anti-CD68 (PGM1) and anti-CD163 antibodies, and the absolute number of intratumoral macrophages in the ATLL specimens was determined. Kaplan-Meier survival estimates were subjected to comparative univariate analyses using the log-rank test. Cox proportional-hazard regression test was used for the multivariate analysis. P-values of less than 0.05 were considered significant.

The number of CD68-positive macrophages in ATLL tissues did not correlate with overall survival (P =0.25), whereas patients with a large number of CD163-positive macrophages (>250 cells/mm² tumor area; n=37) had worse outcomes than those with a small number (<250 cells/mm² tumor area; n=36) (P =0.05). Meanwhile, a higher ratio of CD163-positive to CD68-positive macrophages in ATLL significantly correlated with worse overall survival (P =0.039). Multivariate analysis confirmed that high CD163/CD68 ratio was an independent prognostic factor.

Considering that high CD163/CD68 ratio reflects the proportion of macrophages polarized to the M2 phenotype, our findings further indicate that activation of macrophages towards the M2 phenotype correlates with worse prognosis. They also suggest that immunohistochemical analysis of M2 macrophages at the time of diagnosis can provide additional relevant prognostic information. However, these findings need to be further explored in future studies.

No relevant conflicts of interest to declare.