Mantle cell lymphoma polarizes tumor-associated macrophages into M2-like macrophages, which in turn promote tumorigenesis

Abstract

Tumor-associated macrophages (TAMs) are recognized as a hallmark of certain solid cancers and predictors of poor prognosis; however, the functional role of TAMs in lymphoid malignancies, including B-cell lymphoma, has not been well defined. We identified infiltration of F4/80+ TAMs in a syngeneic mouse model using the recently generated murine mantle cell lymphoma (MCL) cell line FC-muMCL1. Multicolor flow cytometric analysis of syngeneic lymphoma tumors showed distinct polarization of F4/80+ TAMs into CD206+ M2 and CD80+ M1 phenotypes. Using human MCL cell lines (Mino, Granta, and JVM2), we further showed that MCL cells polarized monocyte-derived macrophages toward an M2-like phenotype, as assessed by CD163+ expression and increased interleukin-10 (IL-10) level; however, levels of the M1 markers CD80 and IL-12 remained unaffected. To show that macrophages contribute to MCL tumorigenesis, we xenografted the human MCL cell line Mino along with CD14+ monocytes and compared tumor growth between these 2 groups. Results showed that xenografted Mino along with CD14+ monocytes significantly increased the tumor growth in vivo compared with MCL cells alone (P < .001), whereas treatment with liposomal clodronate (to deplete the macrophages) reversed the effect of CD14+ monocytes on growth of MCL xenografts (P < .001). Mechanistically, IL-10 secreted by MCL-polarized M2-like macrophages was found to be responsible for increasing MCL growth by activating STAT1 signaling, whereas IL-10 neutralizing antibody or STAT1 inhibition by fludarabine or STAT1 short hairpin RNA significantly abolished MCL growth (P < .01). Collectively, our data show the existence of a tumor microenvironmental network of macrophages and MCL tumor and suggest the importance of macrophages in interventional therapeutic strategies against MCL and other lymphoid malignancies.

Cancer risk and gammopathies in 2123 adults with Gaucher disease type 1 in the International Gaucher Group Gaucher Registry

“…Our epidemiologic finding of lower risk for lung cancer is interesting because the lungs have a large population of resident alveolar macrophages which, if they share the characteristics of other Gaucher macrophages as alternatively activated (M2), might be expected to be tumor growth permissive rather than suppressive. 61 Weinreb et al…”

The IL32/BAFF axis supports prosurvival dialogs in the lymphoma ecosystem and is disrupted by NIK inhibition

“…In addition, Mφ-32 shares Mφ-MCL phenotypical and functional characteristics i.e., CD163 mid expression or MCL survival support through soluble dialog, respectively (Figure 6). Only a few studies have addressed the crosstalk between tumor-associated macrophages and MCL cells, so far 12,34,35 . Of note, a recent publication has highlighted that LN infiltrating CD163+ MCL-associated macrophages correlates to a poor prognosis in MCL 36 , suggesting that targeting this interplay could be an interesting perspective for novel therapeutic options.…”

Shaping Polarization Of Tumor-Associated Macrophages In Cancer Immunotherapy

“…This study demonstrated that STAT1-induced NAMPT drives glycolysis, M1 polarization, and better outcomes in both mouse and human models of melanoma, while inhibition of NAMPT with FK866 reverses these effects. However, another study showed that IL-10 secreted by M2 macrophages can promote mantle cell lymphoma growth via the STAT1 signaling pathway ( 36 ). This suggests that STAT1 signaling pathway has complex roles and is involved in both M1 polarization that exerts pro-inflammatory effects and M2 polarization that exerts anti-inflammatory effects.…”