Novel mechanism of immune escape and targeted therapy strategies for liver metastases

Recently, Zeng Zhutian’s team from the Department of Life Science and Medicine of the University of Science and Technology of China published an online report entitled In situ expansion and reprogramming of Kupffer cells elicits potent tumoricidal immunity against liver in the Journal of Clinical Investigation Research paper on metastasis. This study revealed a new mechanism of immune surveillance of hepatic metastatic cancer evading hepatic resident macrophages (KC), developed a new method for in situ targeted amplification and remodeling of KC anti-tumor function, and achieved tumor clearance in a variety of animal models of end-stage liver metastases, thus providing a new idea for the development of immunotherapy strategies for metastatic liver cancer in clinical practice.

Schematic diagram of the principle of Kupffer cell in situ gene editing in the treatment of liver metastases

More than 90% of cancer patients die from tumor metastasis, of which liver metastasis is very common and has a very poor prognosis. At present, the clinical treatment of liver metastases is still limited, and due to the immune tolerance characteristics of the liver, it does not respond well to T cell-based immunotherapy strategies, and it is urgent to develop more effective immunotherapy regimens.

KC, a group of tissue macrophages with the largest number of tissues stationed in the liver, constitute the core link of the liver’s natural immune surveillance because of its super phagocytic function and extremely fast immune response speed. The researchers confirmed that KC plays an important anti-tumor function in the early stage of liver metastasis and dysfunction occurs in the later stage of liver metastasis. Further combining clinical samples and animal models, it was found that liver metastases can gradually induce selective loss of adjacent KCs, so that they cannot enter the cancer foci to exert anti-tumor effects. Based on this discovery, the researchers developed a low-toxicity engineered E. coli carrying CRISPR-CasΦ element that specifically targets KC and enables in situ gene editing. By this method, two key transcription factors c-Maf and MafB that regulate macrophage proliferation and function in KC, the targeted inactivation of KC can induce the rapid expansion of paracancerous KC and the pro-inflammatory function transformation, thereby significantly enhancing the invasion of KC in cancer and its gnawing effect on tumor cells, thereby reshaping the tumor immune microenvironment and inducing a long-term effective anti-tumor T cell response. This strategy effectively achieved tumor clearance in mouse models of end-stage liver metastasis in a variety of tumors, including melanoma, colorectal cancer and lung cancer. This study provides a new method for in situ manipulation of the fate and function of liver macrophages, which has potential application value for the prevention and control of liver diseases such as liver metastases, and also brings new ideas for macrophage-based tumor immunotherapy. (Source: University of Science and Technology of China)

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