On February 1, Journal for ImmunoTherapy of Cancer, the official journal of the Society for Immunotherapy of Cancer (SITC), published online the latest research achievement of Tian Zhigang's research group, “TIPE2 deletion improves the therapeutic potential of adoptively transferred NK cells,” which reported that the expression level of TIPE2 molecules in NK cells in tumor microenvironment is related to the functional depletion state of NK cells, the deletion of TIPE2 by CRISPR/Cas9 technology retards the depletion state of NK cells and significantly enhances the antitumor effect of adoptive NK cells, indicating that targeted deletion of TIPE2 is a potential strategy for promoting NK cell immunotherapy. Tian Zhigang and Sun Haoyu, professors of the University of Science and Technology of China, and Bi Jiacheng, an associate researcher of Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, are the corresponding authors of the paper, and associate researcher Bi Jiacheng is also the first author of the paper.
Screenshot of the published paper
Link of the paper: http://dx.doi.org/10.1136/jitc-2022-006002
The rapid development of immunotherapy is changing the paradigm of tumor treatment. However, not all patients benefit from immunotherapy. In response to solid tumors and other cases, immunotherapy still faces problems such as insufficient effectiveness and safety. On the other hand, under the influence and drive of the concept and technology of synthetic biology, current immunotherapy research is moving towards a new stage of “synthetic immunology” characterized by engineering manipulation. It aims to rationally manipulate the immune response by designing and constructing new synthetic immune molecules, synthetic immune cells, etc., so as to realize the immunotherapy of major diseases such as tumors. The in-depth study of “Immune Checkpoints” (molecules that play an important role in regulating the immune system), an important element in the design of synthetic immune molecules/cells, can not only reveal the regulation law of immune response, but also provide a theoretical basis for the engineering design of synthetic immune molecules/cells. Therefore, the study of “Immune Checkpoints” is the key breakthrough point of the current study of “synthetic immunology”.
Figure 1. NK cells entered a dysfunctional “immunodepletion” state in tumor microenvironment
NK cells (Natural Killer cells) are a kind of innate immune cells that perform immune surveillance on tumors by killing target cells, inducing apoptosis of target cells, or secreting cytokines. A large number of studies have long shown that NK cells not only play a key role in controlling hematological tumors and tumor metastasis, but also their infiltration level in solid tumors is closely related to the prognosis of patients. NK cells play an important role in current tumor immunotherapy research, as they not only recognize and kill tumor cells that escape T cell response such as that have low HLA expression, but also play a role in promoting T cell-based immunotherapy (such as “Immune Checkpoints therapy” targeting PD-1/PD-L1). In addition, NK cells naturally have the advantage of serving as chassis cells in “universal” synthetic immune cell therapy. Nevertheless, NK cells in tumor microenvironment will be negatively regulated by a series of negative immunoregulatory cells, molecules, etc., and enter a dysfunctional “immunodepletion” state (Figure 1) [1,2]; to fully exert the advantages of NK cell-based immunotherapy strategies, researchers need to delve into the functional regulatory mechanisms of tumor-related NK cells.
Figure 2. The expression level of TIPE2 is related to functional depletion of tumor-related NK cells
The research group has previously found that the Immune Checkpoints TIGIT (Hepatology 2014a, 2014b; Nat Immunol 2018), A3AR (Cell Mol Immunol 2021), and TIPE2 (Science Advances 2021) had a negative regulatory effect on the function of NK cells in disease states such as tumors, tissue damage, and regeneration [3-7]. The expression level of intracellular Immune Checkpoint TIPE2 in homeostatic NK cells was related to the functional maturation of NK cells, and mice with conditional deletion of TIPE2 in NK cells showed stronger antitumor function [7]. On the basis of the above studies, researchers further found by means of single-cell transcriptome analysis, reporter gene mice, etc. that the expression level of TIPE2 in human and mouse tumor-related NK cells was related to the functional depletion state of NK cells (Figure 2), and the NK cell subsets with high TIPE2 expression were significantly correlated with poor prognosis of tumor patients.
Figure 3. Deletion of TIPE2 by CRISPR/Cas9 improved adoptive therapy of NK cells
Therefore, the researchers deleted the TIPE2 gene in NK cells from human peripheral blood and NK cells from human induced pluripotent stem cells by CRISPR/Cas9, then induced the functional enhancement state of “memory-like” NK cells through cytokines in vitro, and transferred them to tumor-bearing mice. They found that NK cells with TIPE2 deleted significantly inhibited tumor growth compared to control NK cells, and had an higher infiltration level in tumor tissue (Figure 3). This study showed that targeted deletion of the intracellular Immune Checkpoint TIPE2 could retard the immunodepletion level of NK cells in tumor microenvironment, promote the infiltration and function of NK cells, and thus improve the tumor immunotherapy of adoptive NK cells, suggesting that targeting TIPE2 was a potential strategy to improve NK cell therapy.
This work was supported by programs of the National Key Research and Development Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, Key Laboratory of Quantitative Engineering Biology, Chinese Academy of Sciences, Shenzhen Institute of Synthetic Biology, etc.
References:
[1] Bi J*, Tian Z*. NK Cell Exhaustion. Frontiers in immunology 2017, 8: 760.
[2] Bi J*, Tian Z*. NK cell dysfunction and checkpoint immunotherapy. Frontiers in immunology 2019, 10: 1999.
[3] Bi J, Zhang Q, Liang D, Xiong L, Wei H, Sun R*, Tian Z*. T-cell Ig and ITIM domain regulates natural killer cell activation in murine acute viral hepatitis. Hepatology2014, 59(5): 1715-1725.
[4] Bi J, Zheng X, Chen Y, Wei H, Sun R*, Tian Z*. TIGIT safeguards liver regeneration through regulating natural killer cell-hepatocyte crosstalk. Hepatology 2014, 60(4): 1389-1398.
[5] Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, Wang Z, Wu Q, Peng H, Wei H, Sun R*, Tian Z*. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent antitumor immunity. Nat Immunol 2018, 19(7): 723-732.
[6] Bi J, Zheng C, Zheng X. Increased expression of adenosine A3 receptor in tumor-infiltrating natural killer cells. Cell Mol Immunol 2021, 18(2): 496-497.
[7] Bi J*, Cheng C, Zheng C, Huang C, Zheng X, Wan X, Chen YH, Tian Z, Sun H*. TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity. Science Advances, 2021, 7(38):eabi6515