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Macrophages as a therapeutic key for lung cancer

News 2023-412 EN

Lung cancer is considered the most frequently lethal tumor disease in Western countries. The reasons for this are that lung tumors are often only detected in advanced stages and that conventional therapies have limited effectiveness. DZL scientists at the Max Planck Institute for Heart and Lung Research in Bad Nauheim and Justus Liebig University in Giessen have now shown that the reprogramming of a specific group of white blood cells, known as tumor-associated macrophages, could be a promising approach for cancer therapy.

Reprogramming of macrophages in the tumor environment inhibits tumor growth

Tumor-associated macrophages, abbreviated as TAMs, play a significant role in the progression of lung cancer. This particular group of white blood cells accumulates in the vicinity of the tumor tissue. Previous studies have indicated that the likelihood of an unfavorable course of lung cancer is higher when there are more cells, especially of the M2 subtype, in the tumor tissue environment. In contrast, another subtype, M1-TAM, has a more tumor-inhibiting effect.

In two different research approaches, DZL scientists from the Max Planck Institute for Heart and Lung Research in Bad Nauheim and Justus Liebig University in Giessen attempted to reprogram tumor-associated macrophages from a tumor-promoting to a tumor-inhibiting environment.

"Our strategy aims to reprogram the tumor-promoting M2-TAMs into an M1-like anti-tumor cell type using genetic interventions," explained Rajkumar Savai, who led the studies.

To do this, the research group used a particular type of RNA called long non-coding RNA (lncRNA). This type of RNA influences the transcription process (RNA synthesis based on a DNA template) in many cell types. Savai and his colleagues identified an lncRNA named ADPGK-AS1 in M2-TAMs. "After we activated the macrophages in the experiment, these cells produced a high amount of ADPGK-AS1. Additionally, the RNA shifted from the cytoplasm to the mitochondria and influenced energy production there," said Savai. As a result, ADPGK-AS1 in high concentrations transformed the cells into an M2-like tumor-promoting cell type. To investigate whether the absence of ADPGK-AS1 could have the opposite effect, the scientists used genetic engineering to deactivate it in macrophages. "Indeed, we found that by silencing ADPGK-AS1, both in cell culture and in animal experiments, tumor growth slowed down," Savai explained. "We believe that targeted manipulation of ADPGK-AS1 production in macrophages could be a viable approach for therapy."

In a second study, the scientists also examined the influence of epigenetic regulation of tumor-associated macrophages. They focused on the enzyme Histone Deacetylase 2 (HDAC2). Analysis of biopsies from lung cancer patients revealed a lower survival rate when M2-like macrophages produced a high amount of HDAC2. "Here too, we followed the experimental approach of silencing HDAC2 in M2-TAMs. This actually led to the cells producing more M1-like marker proteins and less M2-like ones," said Savai. In cell culture experiments, this had an impact on the growth of tumor cells: Silencing HDAC2 in TAMs resulted in reduced cell division activity in tumor cells, and more tumor cells died. This was also confirmed in a mouse model: Pharmacological inhibition of HDAC2, which led to a shift in macrophage phenotype from M2 to M1, resulted in delayed tumor growth.

"With these two studies, we have shown that epigenetic changes in macrophages in the tumor environment can enhance the growth of lung tumors," Savai noted. "This creates an immunosuppressive environment that impairs the effectiveness of cancer therapies." Therefore, Savai hopes that by inhibiting epigenetic regulators like ADPGK-AS1 and HDAC2, a therapeutic option has been found. "Immunotherapy targeting these two regulators specifically in lung tumor-associated macrophages could represent a promising new strategy," Savai concluded.


Original publications:

Karger A, Mansouri S, Leisegang MS, Weigert A, Günther S, Kuenne C, Wittig I, Zukunft S, Klatt S, Aliraj B, Klotz LV, Winter H, Mahavadi P, Fleming I, Ruppert C, Witte B, Alkoudmani I, Gattenlöhner S, Grimminger F, Seeger W, Pullamsetti SS, Savai R. ADPGK-AS1 long noncoding RNA switches macrophage metabolic and phenotypic state to promote lung cancer growth. EMBO J. 2023 Sep 18;42(18):e111620. doi: 10.15252/embj.2022111620.

Zheng X, Sarode P, Weigert A, Turkowski K, Chelladurai P, Günther S, Kuenne C, Winter H, Stenzinger A, Reu S, Grimminger F, Stiewe T, Seeger W, Pullamsetti SS, Savai R. The HDAC2-SP1 Axis Orchestrates Protumor Macrophage Polarization. Cancer Res. 2023 Jul 14;83(14):2345-2357. doi: 10.1158/0008-5472.CAN-22-1270.

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