Innovative Immunological Models Unit, Istituto Nazionale Tumori - IRCCS - "Fond G. Pascale", Via Mariano Semmola, 52, Naples, Italy.
Department of Health Technology, Section of Experimental and Translational Immunology, Technical University of Denmark, Kongens Lyngby, Denmark.
J Exp Clin Cancer Res. 2024 Mar 20;43(1):87. doi: 10.1186/s13046-024-03004-z.
We have recently shown extensive sequence and conformational homology between tumor-associated antigens (TAAs) and antigens derived from microorganisms (MoAs). The present study aimed to assess the breadth of T-cell recognition specific to MoAs and the corresponding TAAs in healthy subjects (HS) and patients with cancer (CP).
A library of > 100 peptide-MHC (pMHC) combinations was used to generate DNA-barcode labelled multimers. Homologous peptides were selected from the Cancer Antigenic Peptide Database, as well as Bacteroidetes/Firmicutes-derived peptides. They were incubated with CD8 + T cells from the peripheral blood of HLA-A*02:01 healthy individuals (n = 10) and cancer patients (n = 16). T cell recognition was identified using tetramer-staining analysis. Cytotoxicity assay was performed using as target cells TAP-deficient T2 cells loaded with MoA or the paired TuA.
A total of 66 unique pMHC recognized by CD8+ T cells across all groups were identified. Of these, 21 epitopes from microbiota were identified as novel immunological targets. Reactivity against selected TAAs was observed for both HS and CP. pMHC tetramer staining confirmed CD8+ T cell populations cross-reacting with CTA SSX2 and paired microbiota epitopes. Moreover, PBMCs activated with the MoA where shown to release IFNγ as well as to exert cytotoxic activity against cells presenting the paired TuA.
Several predicted microbiota-derived MoAs are recognized by T cells in HS and CP. Reactivity against TAAs was observed also in HS, primed by the homologous bacterial antigens. CD8+ T cells cross-reacting with MAGE-A1 and paired microbiota epitopes were identified in three subjects. Therefore, the microbiota can elicit an extensive repertoire of natural memory T cells to TAAs, possibly able to control tumor growth ("natural anti-cancer vaccination"). In addition, non-self MoAs can be included in preventive/therapeutic off-the-shelf cancer vaccines with more potent anti-tumor efficacy than those based on TAAs.
我们最近发现肿瘤相关抗原（TAA）与微生物来源抗原（MoA）之间存在广泛的序列和构象同源性。本研究旨在评估健康受试者（HS）和癌症患者（CP）中针对 MoA 和相应 TAA 的 T 细胞识别的广度。
使用> 100 种肽-MHC（pMHC）组合文库生成 DNA 条码标记的多聚体。从癌症抗原肽数据库以及拟杆菌/厚壁菌衍生肽中选择同源肽。将它们与来自 HLA-A*02:01 健康个体（n = 10）和癌症患者（n = 16）外周血的 CD8+T 细胞孵育。使用四聚体染色分析鉴定 T 细胞识别。使用作为靶细胞的 TAP 缺陷型 T2 细胞负载 MoA 或配对 TuA 进行细胞毒性测定。
总共鉴定出 66 种可被所有组的 CD8+T 细胞识别的独特 pMHC。其中，从微生物群中鉴定出 21 个表位作为新的免疫靶标。HS 和 CP 均观察到针对选定 TAA 的反应性。pMHC 四聚体染色证实了与 CTA SSX2 和配对微生物群表位交叉反应的 CD8+T 细胞群体。此外，用 MoA 激活的 PBMC 释放 IFNγ，并且对呈现配对 TuA 的细胞发挥细胞毒性活性。
HS 和 CP 中的 T 细胞识别几种预测的微生物群衍生的 MoA。在 HS 中也观察到针对 TAA 的反应性，这是由同源细菌抗原引发的。在三个受试者中鉴定出与 MAGE-A1 和配对微生物群表位交叉反应的 CD8+T 细胞。因此，微生物群可以引发针对 TAA 的广泛天然记忆 T 细胞反应谱，可能能够控制肿瘤生长（“天然抗癌疫苗接种”）。此外，非自身 MoA 可以包含在预防性/治疗性现成的癌症疫苗中，与基于 TAA 的疫苗相比具有更强的抗肿瘤功效。
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