Prognostic value of diametrically polarized tumor-associated macrophages in multiple myeloma

Abstract

Tumor-associated macrophages (TAMs) are correlated with the prognosis of different types of solid tumors and lymphoma, according to many clinical studies. In vitro experiments have demonstrated the roles of these cells in myeloma cell survival, angiogenesis, immunomodulation, drug resistance, and the interaction between malignant myeloma cells and the microenvironment. Here, we investigated the prognostic significance of TAMs in patients with multiple myeloma (MM). We evaluated the polarized functional status of bone marrow infiltrated by TAMs by immunohistochemical staining of CD68, iNOS, and CD163 in 240 patients with MM from January 2009 to December 2014. The overall response rates to chemotherapy were lower in patients with high CD68+ or CD163+ TAM densities than in those with low densities. Kaplan-Meier analysis showed that the progression-free survival (PFS, p = 0.001) and overall survival (OS, p < 0.001) of patients with low CD163+ TAM density were significantly higher than those of patients with high CD163+ TAM density. Furthermore, combined analysis of iNOS+ and CD163+ TAMs (iNOS/CD163 signature) exhibited greater power in predicting patient outcomes for both PFS (p < 0.001) and OS (p < 0.001). Moreover, Cox regression analysis identified iNOS+ and CD163+ TAMs as independent prognostic factors (p = 0.007, p < 0.001, respectively). These factors could be combined with the international staging system (ISS) to generate a predictive nomogram for patient outcomes. Our findings suggest that the mosaic of diametrically polarized TAMs is a novel independent prognostic factor that could be integrated into the evaluation of and therapy for MM.

CD4+ T-cell killing of multiple myeloma cells is mediated by resident bone marrow macrophages

“…43,44 High levels of macrophage infiltration, in particular cases with a dominance of macrophages with M2-like phenotypic traits have been reported to be negative prognostic factors for myeloma patient survival. [45][46][47] In line with previous reports, 14 we found that intact IFN-g signaling was necessary for macrophage-mediated tumor rejection. Although we have previously shown that intratumoral delivery of IFN-g may significantly delay tumor outgrowth in a T-cell-independent manner, presumably through direct effects on tumor-associated macrophages, 14 IFN-g in itself is insufficient to induce a tumoricidal phenotype in tumor-associated macrophages ex vivo, 22 suggesting that this cytokine is required, but not sufficient for tumor rejection.…”

Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice

“…On the other hand, polarization of TAMs toward the M2 phenotype as reflected by lower M1/M2 ratio was an independent predictor for poor response to CT or RT and shorter survival in LACC (39). This was supported by other studies involving different cancer types such as ovarian cancer (40), pediatric classical Hodgkin lymphoma (cHL) (41), and multiple myeloma (42).…”

Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma

“…2B and Table S3). Clustering the plasma cells of MGUS04 shows that the malignant cells (in cluster 4) are characterized by a transcriptional signature overexpressing a known MM driver (CCND1), along with DPEP3 (p<1x10 -50 ), a dipeptidase involved in arachidonic acid metabolism, previously associated with triple negative breast cancer, but not with MM (Table S2) 41 . These malignant PC originate from a single BCR clonotype.…”