Immunology Unit, Department of Cell Biology, Physiology and Immunology, Institut de Biotecnologia i Biomedicina (IBB), Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain.
Translational Molecular Pathology, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain.
Front Immunol. 2021 Nov 16;12:761798. doi: 10.3389/fimmu.2021.761798. eCollection 2021.
EBV-specific T cells have been recently described to be involved in fatal encephalitis and myocarditis in cancer patients after immune checkpoint therapies. Here, we report the study of a human triple-negative breast cancer tumor (TNBC) and EBV-transformed B cells obtained from a patient-derived xenograft (PDX) that progressed into a lymphocytic neoplasm named xenograft-associated B-cell lymphoma (XABCL). T-cell receptor (TCR) high-throughput sequencing was performed to monitor the T-cell clonotypes present in the different samples. Forty-three T-cell clonotypes were found infiltrating the XABCL tissue after three passes in mice along 6 months. Eighteen of these (42%) were also found in the TNBC biopsy. TCR infiltrating the XABCL tissue showed a very restricted T-cell repertoire as compared with the biopsy-infiltrating T cells. Consequently, T cells derived from the TNBC biopsy were expanded in the presence of the B-cell line obtained from the XABCL (XABCL-LCL), after which the TCR repertoire obtained was again very restricted, i.e., only certain clonotypes were selected by the B cells. A number of these TCRs had previously been reported as sequences involved in infection, cancer, and/or autoimmunity. We then analyzed the immunopeptidome from the XABCL-LCL, to identify putative B-cell-associated peptides that might have been expanding these T cells. The HLA class I and class II-associated peptides from XABCL-LCL were then compared with published repertoires from LCL of different HLA typing. Proteins from the antigen processing and presentation pathway remained significantly enriched in the XABCL-LCL repertoire. Interestingly, some class II-presented peptides were derived from cancer-related proteins. These results suggest that bystander tumor-infiltrating EBV+ B cells acting as APC may be able to interact with tumor-infiltrating T cells and influence the TCR repertoire in the tumor site.
EBV 特异性 T 细胞最近被描述为参与免疫检查点治疗后癌症患者致命性脑炎和心肌炎。在这里，我们报告了一项人类三阴性乳腺癌肿瘤（TNBC）和从患者衍生的异种移植（PDX）中获得的 EBV 转化 B 细胞的研究，该 PDX 进展为称为异种相关 B 细胞淋巴瘤（XABCL）的淋巴细胞肿瘤。进行了 T 细胞受体（TCR）高通量测序，以监测存在于不同样本中的 T 细胞克隆型。在 6 个月的时间里，经过三次传代，在小鼠中发现了 43 种浸润 XABCL 组织的 T 细胞克隆型。其中 18 种（42%）也存在于 TNBC 活检中。与活检浸润 T 细胞相比，浸润 XABCL 组织的 TCR 显示出非常受限的 T 细胞 repertoire。因此，在来自 XABCL 的 B 细胞系（XABCL-LCL）存在的情况下，从 TNBC 活检中扩增 T 细胞，然后获得的 TCR repertoire 再次非常受限，即只有某些克隆型被 B 细胞选择。其中一些 TCR 先前已被报道为参与感染、癌症和/或自身免疫的序列。然后，我们分析了 XABCL-LCL 的免疫肽组，以鉴定可能正在扩增这些 T 细胞的 B 细胞相关肽。然后将 XABCL-LCL 的 HLA 类 I 和类 II 相关肽与来自不同 HLA 分型的 LCL 的已发表库进行比较。来自抗原加工和呈递途径的蛋白质在 XABCL-LCL 库中仍然显著富集。有趣的是，一些 II 类呈递的肽来自癌症相关蛋白。这些结果表明，作为 APC 的旁观者肿瘤浸润性 EBV+B 细胞可能能够与肿瘤浸润性 T 细胞相互作用，并影响肿瘤部位的 TCR repertoire。
