CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Identification of antigenic epitopes recognized by tumor infiltrating lymphocytes in high grade serous ovarian cancer by multi-omics profiling of the auto-antigen repertoire.
Identification of antigenic epitopes recognized by tumor infiltrating lymphocytes in high grade serous ovarian cancer by multi-omics profiling of the auto-antigen repertoire.
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旨在增强肿瘤特异性T细胞杀伤癌细胞的免疫治疗策略，有望降低肿瘤负荷并延长癌症患者生存期。虽然已有许多潜在肿瘤抗原被报道，在设计抗癌疫苗或靶向细胞疗法时，确定相关靶点仍是一项挑战。为识别新型且可能具有免疫原性的候选肿瘤抗原，我们对高级别浆液性卵巢癌（HGSC）患者肿瘤样本开展了肿瘤转录组、血清组和蛋白质组整合分析。
我们利用全外显子组及RNA测序识别肿瘤新抗原和过表达抗原，并将其与患者配对自身抗体库进行比较。研究重点是CD8⁺ T细胞识别的MHC I类表位；我们从高表达、突变或自身抗体靶抗原，以及MHC相关肽（MAP）中识别或预测HLA结合表位。通过检测每位患者扩增的TIL（肿瘤浸润淋巴细胞）群体，评估其对候选抗原肽的识别。已知肿瘤相关抗原（TAA）和癌睾抗原（CTA）常见于自身抗体和MAP库中，也检测到识别这些抗原表位的CD8⁺ TIL；但抗原表达水平和自身抗体存在与否均与TIL识别无相关性。多数患者存在针对肿瘤突变抗原的自身抗体，但未检测到TIL识别预测亲和力最高的新表位。结合高表达水平、自身抗体识别和表位预测算法，我们发现5种新型抗原（MOB1A、SOCS3、TUBB、PRKAR1A、CCDC6）中的表位可被HGSC患者TIL识别。
此外，从MAP库筛选表位还发现了5种其他可被多名患者TIL共同识别的靶点。我们发现，TIL特异性库包含针对肿瘤加工并呈递的高表达、具有免疫原性的自身抗原的识别。结果提示，HGSC TIL针对多种自身抗原持续产生自身免疫应答。
Immunotherapeutic strategies aimed at enhancing tumor cell killing by tumor-specific T cells hold great potential for reducing tumor burden and prolonging survival of cancer patients. Although many potential tumor antigens have been described, identifying relevant targets when designing anti-cancer vaccines or targeted cell therapies remains a challenge.
To identify novel, potentially immunogenic candidate tumor antigens, we performed integrated tumor transcriptomic, seromic, and proteomic analyses of high grade serous ovarian cancer (HGSC) patient tumor samples.
We identified tumor neo-antigens and over-expressed antigens using whole exome and RNA sequencing and examined these in relation to patient-matched auto-antibody repertoires. Focusing on MHC class I epitopes recognized by CD8 + T cells, HLA-binding epitopes were identified or predicted from the highly expressed, mutated, or auto-antibody target antigen, or MHC-associated peptides (MAPs). Recognition of candidate antigenic peptides was assessed within the tumor-infiltrating T lymphocyte (TIL) population expanded from each patient.
Known tumor-associated antigens (TAA) and cancer/testis antigens (CTA) were commonly found in the auto-antibody and MAP repertoires and CD8 + TILs recognizing epitopes from these antigens were detected, although neither expression level nor the presence of auto-antibodies correlated with TIL recognition.
Auto-antibodies against tumor-mutated antigens were found in most patients, however, no TIL recognition of the highest predicted affinity neo-epitopes was detected. Using high expression level, auto-antibody recognition, and epitope prediction algorithms, we identified epitopes in 5 novel antigens (MOB1A, SOCS3, TUBB, PRKAR1A, CCDC6) recognized by HGSC patient TILs.
Furthermore, selection of epitopes from the MAP repertoire identified 5 additional targets commonly recognized by multiple patient TILs.
We find that the repertoire of TIL specificities includes recognition of highly expressed and immunogenic self-antigens that are processed and presented by tumors. These results indicate an ongoing autoimmune response against a range of self-antigens targeted by HGSC TILs.
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