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Tumor immunotherapy represented by PD1 antibody has made great progress in recent years, changing the treatment mode of tumors, but the current response rate is less than 30%, and the effect on liver cancer and colorectal cancer is particularly poor, so it is urgent to develop new tumor immunotherapy strategies and targets. NK cells play an important role in tumor immunity, with the characteristics of fast response, wide tumor suppression spectrum, good versatility and low toxicity, and are becoming a new track of global competition, but due to the unique local microenvironment of tumors, conventional NK (cNK) cells have bottlenecks such as "difficult to enter tumor tissue" and "function is inhibited after entry". In addition to cNK, there are a large number of type 1 innate lymphoid cells (ILC1s) in the liver, intestine and other tissues. ILC1s, also known as tissue-resident NK cells, have been found to have both pro-tumor and anti-tumor activities in recent years, but due to their great phenotypic similarity with cNK cells, there is currently a lack of intervention methods targeting ILC1s, and its function in tumor immunity is still unclear.
On October 2, 2024, the team of Rongbin Zhou/Wei Jiang/Xiaqiong Wang, Department of Life Science and Medicine, Key Laboratory of Immune Response and Immunotherapy, University of Science and Technology of China, published a research paper titled GPR34 is a metabolic immune checkpoint for ILC1-mediated antitumor immunity online in Nature Immunology. It has been reported that the tumor-derived lipid metabolite lysophosphatidylserine (LysoPS) can inhibit the anti-tumor activity of ILC1s through its receptor GPR34, and antagonizing the GPR34 receptor can induce potent ILC1s-mediated anti-tumor immunity to inhibit the growth of solid tumors such as liver cancer and colorectal cancer.
In this study, the researchers constructed a tdTomato-GPR34 reporter mouse and found that GPR34 was highly expressed on ILC1s but not on cNK cells, suggesting that GPR34 could be used as a new marker to distinguish between ILC1s and cNK. Using a variety of different models of subcutaneous tumors and colon cancer liver metastases, the researchers found that GPR34 systemic gene defects or ILC1s condition defects could increase the proportion, number and anti-tumor activity of ILC1s in tumors, and inhibit tumor growth, indicating that GPR34 promotes tumor growth by inhibiting the anti-tumor activity of ILC1s.
Next, the researchers explored the mechanism by which GPR34 regulates ILC1s-mediated anti-tumor immunity. By mass spectrometry, it was found that the GPR34 ligand LysoPS accumulated in the tumor interstitial fluid. In vitro experiments showed that LysoPS inhibited the activation of ILC1s via the cAMP-PKA-CREB pathway in a GPR34-dependent manner. Knockdown of the expression of LysoPS synthase ABHD16A on tumor cells can reduce the level of LysoPS in tumor interstitial fluid and inhibit tumor growth. In addition, inhibition of LysoPS production in tumors can increase the number, proportion, and anti-tumor activity of ILC1s in tumors. These results suggest that tumor-derived LysoPS inhibits ILC1s-mediated tumor immunity through GPR34 and thereby promotes tumor growth.
Further studies have found that blocking GPR34 with inhibitors can inhibit tumor growth in both subcutaneous tumor models and liver metastasis models, and the combination of GPR34 inhibitors and anti-TIGIT antibodies can improve the efficiency of tumor treatment.
Finally, the researchers explored the clinical relevance of the LysoPS-GPR34-ILC1s pathway in human cancer, and found that GPR34 mRNA was highly expressed on ILC1-like cells in tumor tissues of patients with colon adenocarcinoma, head and neck cancer, or hepatocellular carcinoma, but low on cNK cells, and the expression of ABHD16A and GPR34 was negatively correlated with the antitumor activity of ILC1s in cancer patients.
In summary, the study found that the tumor-derived lipid metabolite LysoPS can inhibit the anti-tumor activity of ILC1s through its receptor GPR34, while antagonizing GPR34 can enhance the anti-tumor activity of ILC1s and inhibit tumor growth. The innovation of the study is reflected in: 1) it was the first to demonstrate that targeting ILC1s (tissue-resident NK) can induce anti-tumor immunity and inhibit tumor growth, suggesting that targeting tissue-resident immune cells may be a potentially effective strategy for solid tumors; 2) Discovery of the danger signal-sensing receptor GPR34 as a new metabolic immune checkpoint.
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https://www.nature.com/articles/s41590-024-01973-z
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