Cancer Cell recognizes human lung cancer antigens

Written | My best friend, the old red hat, in the past three decades, a series of tumor antigens that can be recognized by T cells have been discovered [1], and the tumor antigens encoded by tumor-specific somatic mutations and the efficacy of immunotherapy This is closely related, and even more, studies have given evidence of a direct correlation between the efficacy of immunotherapy and somatic mutations in tumor lesions, for example, immunotherapy is more likely to work in cancer patients with abnormal DNA damage repair [ 2,3], while a study on melanoma infiltrating lymphocytes found that T cell-specific antigens encoded by somatic mutations were found in half of the patients [4]

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Tumor antigens are one of the safest immune targets because they are not expressed in normal tissues.

However, how T cells discover and recognize these tumor antigens is still a big problem

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The discovery of tumor antigens is usually achieved by algorithms based on major histocompatibility complexes, but this approach does not take into account the question of whether T cells can specifically recognize antigens

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In fact, a large-scale study in 2019 found that only 1.6% of antigens could be recognized by T cells [5]

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Therefore, there is an urgent need to establish a method that can rapidly discover antigens that T cells can recognize

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On April 21, 2022, James C.

Yang's research group from the National Institutes of Health published an article in Cancer Cell entitled A phenotypic signature that identifies neoantigen-reactive T cells in fresh human lung cancers, which defines the identification of tumors Molecular signature of antigenic T cells

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TCR-CITE sequencing enables rapid analysis and integration of cell surface molecular, cellular transcriptome, and T cell receptor (TCR) information at the single-cell level

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Therefore, if a cell's TCR sequence is known, its transcriptome and cell surface molecule expression can also be predicted
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The authors first recruited 4 patients with non-small cell lung cancer, and performed amplification and whole exome sequencing of lymphoid infiltrating cells in their tumor lesions.
Identify tumor-mutated TCRs
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Among them, 7 groups were derived from CD8+ T cells, and 4 groups were derived from CD4+ T cells
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Next, the authors compared each patient's tumor-specific CD8+ T cells with other CD8+ T cells at the protein and gene levels, and identified 24 groups of molecules that were significantly altered in several patients, including 22 groups that were up-regulated and 2 groups down
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Among them, CD39 and CD103 are highly expressed in tumor antigen-specific T cells
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In addition, up-regulated molecules include CXCL13[6,7], PDCD1, LAYN, CD27, BATF, TIGIT and MIR55HG, and down-regulated molecules include IL7R
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Among the four patients, three CD8+ T cells expressed CD39 in 23% to 34%, while the fourth patient, the only patient who received anti-PD-1 antibody treatment, expressed only 5.7 % of CD8+ T cells express CD39
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The proportion of CD8+ T cells expressing CXCL13 fluctuated between 2.5% and 11.1%
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The content of antigen-specific CD4+ T cells is relatively small.
The authors integrated data from multiple sources and determined that CD4+ T cells that recognize tumor antigens also highly express CD39, TIGIT, and CXCL13
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Among them, CD39+ T cells basically also highly express TIGIT, and such CD39+ TIGIT+ cells can be divided into two subtypes, one is FoxP3+ Treg, the other is CXCL13+ and contains basically all the tumor antigens that can specifically recognize clone
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Finally, the authors analyzed 985 CD8+ T cells and 303 CD4+ T cells that could recognize tumor antigens, and found that among these CD8+ T cells, CD39, CD103 and PD-1 were highly expressed, CD4, CD8A, CD45RA, Low expression of CD62L and CD134
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Transcriptome analysis of CD8+ T cells recognizing tumor antigens identified upregulation of CXCL13, ENTPD1, ​​LAYN, TIGIT, BATF, GZMB, CD27 and PHLDA1, while downregulation of CD127
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CXCL13, ENTPD1, ​​ADGRG1, NMB, ITM2A, NR3C1 and ETV7 were highly expressed in CD4+ T cells
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In conclusion, the authors identified a set of CD39 and CXCL13-based molecular signatures of T cells that can rapidly recognize tumor antigens by analyzing the transcriptome and TCR of tumor-infiltrating lymphocytes from four patients with non-small cell lung cancer
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Of course, the sample size of 4 patients is relatively small, and whether the above results are universal remains to be discussed
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Original link: https://doi.org/10.1016/j.ccell.2022.03.012

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