Cell subdominant antigens in tumors determine the phenotype of TCF1+CD8+T precursor cells

Written | My girlfriend, Red Riding Hood, has multiple evidences that neoantigens, which are peptides produced by mutations in major histocompatibility molecules, can drive T cells to respond to tumors [1]
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After tumor immune checkpoint suppression therapy (such as anti-PD-1), neoantigen-specific CD8+ T cells proliferate significantly, and this proliferation is positively correlated with the level of neoantigen [2]; and the adoptiveness of targeting neoantigens T cell therapy can obviously play an anti-cancer effect [3,4]
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These results show that immunotherapy methods targeting neoantigens have very broad prospects in cancer treatment, especially in the development of cancer vaccines
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However, its specific mechanism and how to apply it to cancer treatment are still poorly understood
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In order to study in detail the response process of T cells to tumors and the relationship with neoantigens, the Tyler Jacks research group from the Massachusetts Institute of Technology recently published in the Cell magazine titled Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes In tumors research article, it is found that in lung cancer models, subdominant neoantigens are more likely to cause T cell responses, and that immune checkpoint therapy can achieve better curative effects in the treatment of lung cancer
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First, the author constructed two CD8+ T cell neoantigens, SIIN (SIINFEKL) and SIY (SIYRYYGL) linked to the luciferase reporter gene, and based on this, established mouse lung adenocarcinoma expressing these tumor-specific neoantigens Model (LucOS)
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The authors found that SIIN and SIY have superiority levels, that is, one is a dominant antigen and the other is a subdominant antigen
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At 5 weeks, SIIN induces a significantly higher level of CD8+ T cells than SIY, but the duration is short, while SIY can continue to induce a stable level of CD8+ T cells
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Finally, around 12 weeks, the levels of CD8+ T cells induced by the two were basically the same
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Next, the author further studied the difference between SIIN and SIY-specific CD8+ T cells
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Using single-cell RNA sequencing, the author found that SIIN-specific cells tend to express effector T cell tags, while SIY-specific cells tend to express naive T cell and memory precursor T cell tags
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A number of recent reports have pointed out that immune checkpoint suppression therapy can promote the differentiation of precursor cells.
It can also be understood that the level of precursor cells is closely related to the efficacy of immune checkpoint suppression therapy
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Precursor cells usually express TCF1 (transcription factor T cell factor 1), which is also consistent with the molecular signature expressed by SIY-specific cells
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Because SIIN induces a higher level of CD8+ T cells than SIY, the authors speculate that this result of competition is likely to be related to the TCF+ precursor cells induced by SIY
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To confirm this hypothesis, the authors constructed mice expressing SIY and SIIN alone (LucSIIN and LucSIY), and found that SIY alone could not induce high levels of TCF1+ precursor T cells
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This also shows that there is an antigen level in tumors, and the response to subdominant antigens is crucial in the anti-cancer process
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In immune checkpoint suppression therapy, TCF+ precursor cells play a key role in CD8+ T cell response.
The authors studied whether SIY-specific cells also play a key role in this treatment
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After one week of anti-PD-1/CTLA-4 treatment, T cell proliferation was more obvious, and its dynamic changes were basically the opposite of TCF1+ precursor T cells
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In other words, immune checkpoint therapy makes the cell type change from TCF1+ to TCF1-
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However, although the proportion of TCF1+ cells is gradually decreasing, their absolute number is increasing
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Another interesting result showed that despite the increased levels of TCF+T cells, the response of SIY-specific cells to immune checkpoint suppression therapy was not more pronounced than that of SIIN
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In order to further explain these phenomena, the authors found that the SIY-specific cell label significantly overlapped with Tc17 cells
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Tc17 cells are a type of CD8+ T cell subtype that express the chemokine receptor CCR6 and produce the cytokine IL-17A, and are usually associated with autoimmune inflammation
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Next, the author further confirmed by flow cytometry that both SIIN and SIY-specific cells were positive for CCR6, and SIY-specific cells were more obvious; moreover, most CCR6+ cells also expressed TCF1; in addition, SIY-specific cells The level of IL-17A expressed and secreted by the cells is also higher.
These results indicate that the level of Tc17 differentiation is higher in SIY-specific cells
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Next, the author pays attention to the specific functions of this type of CCR6+TCF1+Tc17
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The author connected a fluorescent reporter gene to IL-17A and determined that the vast majority of SIY-specific CCR6+ cells express IL-17A
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It is worth noting that IL-17A+ cells cannot differentiate into cytotoxic cells, even in the treatment of anti-PD-1/CTLA-4, that is, the anti-cancer effect of such cells is not obvious
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Moreover, after immune checkpoint treatment, the level of IL-17A+ cells was significantly reduced, showing that anti-cancer treatment can inhibit the Tc17 cell pathway
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In autoimmune diseases, self-antigens can up-regulate the expression of CCR6 and the level of Tc17 differentiation [5], so the author speculates that this phenomenon is probably caused by the pre-stimulation of T cells
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The authors found that the T cell level and cytotoxicity of tumor-bearing mice pre-stimulated by SIY and SIIN polypeptides both increased significantly, and the effect of SIY was more significant
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Moreover, compared with SIIN/SIY and SIIN alone pre-stimulation, SIY still induced high levels of TCF1+ precursor cells and differentiated Tc17, while CCR6+TCF1+ cells were basically depleted
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Finally, the author confirmed by analyzing the existing human cancer single-cell sequencing results that CCR6+TCF+ cells and Tc17 cells are present in a variety of human cancer lesions, which also laid a theoretical foundation for the application of this work to the clinic
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To sum up, the authors found that tumor antigens have a dominant level phenomenon through a mouse lung adenocarcinoma model.
Subdominant antigens can induce more significant T cell responses, and tend to exhibit TCF1+ T cell phenotypes and interact with immune checkpoints.
Suppressive treatment is related to efficacy
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Of course, the opposite immunotherapy cannot enhance the induction of subdominant antigens, which is related to the level of differentiation of CCR6+TCF+ cells and Tc17 cells
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Finally, the author believes that antigen pre-stimulation can significantly down-regulate the level of CCR6+TCF1+T cells, thereby enhancing the anti-cancer effect of immunotherapy
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Original link: https://doi.
org/10.
1016/j.
cell.
2021.
08.
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