Macrophages play a critical role in both innate and adaptive immunity, essential for maintaining tissue homeostasis and combating infections. In the context of cancer, macrophages can differentiate into two main phenotypes: M1 macrophages, which exhibit anti-tumor properties, and M2 macrophages, which support tumor progression and contribute to anti-inflammatory responses. The ratio of M1 to M2 macrophages within the tumor microenvironment (TME) is vital for anti-tumor immunity, presenting a significant target for new cancer therapies.
Researchers at George Washington University (GW) have developed a novel approach to reprogram macrophages ex vivo into an anti-tumor M1 phenotype by utilizing STAT inhibitors and a selective HDAC6 inhibitor. HDAC6 inhibitors (HDAC6is) are known to modulate immune responses by polarizing macrophages towards the M1 phenotype and enhancing their antigen-presenting capacity. This immune modulation is achieved through the STAT3-PP2A pathway, where HDAC6 regulates the dephosphorylation of STAT3, altering the expression of STAT3-target genes and effectively promoting the M1 phenotype. The researchers discovered that isolated macrophages treated with STAT inhibitors outside the body (ex vivo) are effectively reprogrammed towards the anti-tumor M1 phenotype. These reprogrammed macrophages, termed STAT-activated macrophages, can then be administered to patients to treat cancer and other diseases, providing a targeted approach to attack cancer cells while minimizing the side effects commonly associated with chemotherapy.
This innovative immunotherapy strategy has the potential to improve treatment outcomes for patients with various types of tumors by harnessing and reprogramming the body’s innate immune response, creating new therapeutic opportunities for combating cancer and other immune-related diseases.
Figure. Ex-vivo treatment of BMDMs reduces M2 macrophage polarization: Bone marrow-derived macrophages (BMDMs) from C57BL/6 mice were differentiated using mouse recombinant macrophage-colony stimulating factor (M-CSF). These naïve (unpolarized) macrophages (M0) were then polarized to the M2 phenotype in the presence or absence of the HDAC6 inhibitor, NextA or STAT 3 inhibitor, Stattic. M2 polarization was evaluated by measuring the cell surface expression of, CD206+ macrophages.
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