Tumor-Associated Macrophages Mediate Immunosuppression in the Renal Cancer Microenvironment by Activating the 15-Lipoxygenase-2 Pathway

Abstract

Renal cell carcinoma (RCC), the most common human kidney cancer, is frequently infiltrated with tumorassociated macrophages (TAM) that can promote malignant progression. Here, we show that TAMs isolated from human RCC produce substantial amounts of the proinflammatory chemokine CCL2 and immunosuppressive cytokine IL-10, in addition to enhanced eicosanoid production via an activated 15-lipoxygenase-2 (15-LOX2) pathway. TAMs isolated from RCC tumors had a high 15-LOX2 expression and secreted substantial amounts of 15(S)-hydroxyeicosatetraenoic acid, its major bioactive lipid product. Inhibition of lipoxygenase activity significantly reduced production of CCL2 and IL-10 by RCC TAMs. In addition, TAMs isolated from RCC were capable of inducing in T lymphocytes, the pivotal T regulatory cell transcription factor forkhead box P3 (FOXP3), and the inhibitory cytotoxic T-lymphocyte antigen 4 (CTLA-4) coreceptor. However, this TAMmediated induction of FOXP3 and CTLA-4 in T cells was independent of lipoxygenase and could not be reversed by inhibiting lipoxygenase activity. Collectively, our results show that TAMs, often present in RCCs, display enhanced 15-LOX2 activity that contributes to RCC-related inflammation, immunosuppression, and malignant progression. Furthermore, we show that TAMs mediate the development of immune tolerance through both 15-LOX2-dependent and 15-LOX2-independent pathways. We propose that manipulating LOX-dependent arachidonic acid metabolism in the tumor microenvironment could offer new strategies to block cancer-related inflammation and immune escape in patients with RCC. Cancer Res; 71(20); 6400-9. Ó2011 AACR.

BMP-6 in Renal Cell Carcinoma Promotes Tumor Proliferation through IL-10–Dependent M2 Polarization of Tumor-Associated Macrophages

“…Recently, it has been suggested that a local production of IL-10 results in a tumor microenvironment that favors cancer cell survival and metastases (23,27). In RCC, IL-10 and IL-10 receptor expression has been correlated with increased incidence of metastasis (28). Nevertheless, the clinical significance of IL-10 and the mechanism of its induction in cancers remain largely unknown.…”

Tumor-Associated Macrophages: Implications in Cancer Immunotherapy

“…As the regulatory functions of T reg is governed by a pivotal transcription factor, Foxp3 in CD4 + T cells, it is not surprising to find that TAMs promote the expression of Foxp3 via IL-10 and TGF-β signaling [4,64,67,68]. Direct evidence also showed the induction of Foxp3 and CTLA4 expression in CD4 + T cells by TAMs in human renal cell carcinoma in vivo, further emphasizing the critical role of TAMs in cancer-related inflammation, immunosuppression and malignant progression [69].…”

Role of tumor-associated macrophages in renal cell carcinoma pathogenesis

“…Это объ-ясняется экспрессией мембранной формы M-CSF на поверхности опухолевых клеток [31]. Другое иссле-дование, описывающее популяцию МАО, изолирован-ную из опухолей почки, выделяет экспрессию CD68 и CD163, но не CD206 на поверхности макрофагов [32]. Далее в своем исследовании авторы показали, что МАО, изолированные из опухоли, продуцируют значительное количество CCL-2 -СС-хемокина, ко-торый привлекает новые моноциты в опухоль.…”

“…В то же время эти макрофаги продуцируют большое количест-во ИЛ-10. В частности, авторы продемонстрировали, что МАО из более крупных опухолей продуцируют большее количество ИЛ-10 [32]. В своем исследовании I. Daurkin и соавт.…”

“…В своем исследовании I. Daurkin и соавт. показали, что макрофаги, изолиро-ванные из опухолей светлоклеточного рака почки, про-дуцируют большое количество эйкозаноидов посред-ством активации зависимого сигнального пути 15-липоксигеназы-2 [32], что типично для макрофагов при активации их TGF-β1 (transforming growth factor β1) [10]. Неожиданным является тот факт, что МАО из опухолей почки экспрессируют CCR8 посредством активации Stat3-зависимого сигнального пути, что бо-лее характерно для воспалительного фенотипа макро-фагов.…”