"Nature" heavy: Li Ming's team discovered a new type of anti-cancer T cells!

▎WuXi AppTec Content Team Editor On April 20, Zhou Jun, Zhang Zhen and collaborators from Professor Li Ming's laboratory at Memorial Sloan-Kettering Cancer Center published a paper in the journal Nature, revealing that an immune A new mechanism of anti-cancer, and the discovery of a T cell with great anti-cancer potential is expected to promote the development of immunotherapy in a new direction
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When the human body resists cancer invasion, cancer immune monitoring is a very critical link
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In this process, the immune system can remove potentially cancerous transformed cells, and mainly rely on traditional CD8+ T cells to recognize tumor neoantigens and kill cancer cells
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According to Professor Li Ming, tumor neoantigens generally refer to antigens that can be recognized by T cell receptors only after somatic mutation in tumor cells
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In contrast, there is a class of tumor-native antigens that can be recognized by T-cell receptors without mutation
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Although the immune system can closely monitor the abnormal behavior of cancer cells, cancer cells do not sit still.
They cunningly upregulate the immunosuppressive PD-L1, which binds to the PD-1 receptor in traditional CD8+ T cells.
to inhibit T cell function and even induce T cell exhaustion
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Image source: 123RF Now many drugs targeting PD-1 or PD-L1 can restore T cell function to a certain extent, but their efficacy is still limited by the amount of tumor neoantigens, and it is not applicable to all cancer types
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Therefore, scientists are also working hard to find other T cells with cancer-fighting potential
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In the latest "Nature" study, the research team discovered a T cell that lacks PD-1 but highly expresses the natural killer cell receptor.
Based on the characteristics of this type of T cell, the research calls it innate killer T-like Cell (Killer Innate-like T cell, ILTCK)
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It is so named because, unlike traditional CD8+ T cells, ILTCK is independent of dendritic cells for activation and has properties more similar to innate lymphocytes
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▲ILTCK has different differentiation characteristics from traditional T cells (Image source: Reference [1]) The most noteworthy thing is that, unlike traditional CD8+ T cells, the newly discovered ILTCK does not express PD-1 and other immunosuppressive receptors.
Therefore, it does not enter into a state of cell depletion
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This means that ILTCK can evade cancer cells more easily
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The research team did observe that ILTCK exhibited stronger cytotoxicity on tumor cells
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The biggest difference between these newly discovered ILTCKs and traditional T cells is that most traditional T cells tend to recognize tumor neoantigens, but ILTCKs recognize tumor native antigens
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This endows ILTCK with an extremely powerful ability: it can play a better role in tumors where native antigens are spread, and because it does not express PD-1 and does not experience cell exhaustion, it can be described as an anti-cancer T cell that can continue to develop type
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Under normal circumstances, during the differentiation process of T cells, T cells that can recognize the host's native antigen are usually eliminated, so as to avoid autoimmune diseases
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So how does ILTCK recognize native antigens while avoiding autoimmune diseases? Professor Li Ming's team told us that there may be two reasons for this
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The first is that according to their observation, the cytotoxicity of ILTCK requires interleukin 15 (IL-15) to activate
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However, in healthy tissues, IL-15 is not expressed at high levels, on the contrary, IL-15 is greatly up-regulated in cancer cells
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This allows ILTCK to target cancer cells rather than normal healthy tissue
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The second point is that during the differentiation of ILTCK, the recognition of the autologous native antigen will inhibit the downstream signaling of the T cell receptor, which means that in the absence of other activation signals, the cytotoxicity of ILTCK cannot be induced by the native antigen alone
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With both safeguards, our healthy tissues can be safe from autoimmune diseases
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▲IL-15 plays an important role in the cytotoxicity of ILTCK (Image source: Reference [1]) The research team also verified the key role of IL-15 in the experiment.
Once the expression of IL-15 is inhibited in cancer cells , then the amount of ILTCK in the tumor and its function will be greatly reduced, so that the tumor can continue to grow rapidly
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Therefore, the study also suggests that monitoring the expression of IL-15 is likely to be a new cancer immune monitoring mechanism, which plays an important role in mediating the anticancer process of ILTCK
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Professor Li Ming's team first discovered ILTCK in a mouse breast cancer model in 2016 and revealed some of its anticancer properties
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After nearly 6 years of research, they have a more comprehensive understanding of the origin and anti-cancer mechanism of ILTCK.
ILTCK is more likely to be a type of immune cell between innate lymphocytes and traditional T cells
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In addition, this study further found that ILTCK-like immune cells also exist in human cancer tissues
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Professor Li Ming pointed out that the discovery of ILTCK not only opened up new ideas for tumor immunotherapy, but also provided a new perspective for the evolution of T cell lines
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The research team is very much looking forward to the potential applications of this new discovery.
Most of the past tumor immune cognition and related therapies are based on the traditional T cell-centered framework
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Today, the emergence of ILTCK means that we can hope to break away from this framework.
Its unique performance and superiority over traditional T cells are expected to provide new solutions for long-term solid tumors, and further optimize the current some immunotherapy
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Reference: [1] Chun Chou, Xian Zhang, et al.
Programme of self-reactive innate-like T cell-mediated cancer immunity.
Nature(2022).
DOI: 10.
1038/s41586-022-04632-1[2] Dadi S et al.
, Cancer Immunosurveillance by Tissue-Resident Innate Lymphoid Cells and Innate-like T Cells.
Cell.
2016 Jan 28;164(3):365-77.
doi: 10.
1016/j.
cell.
2016.
01.
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