Targeting nonviral antigens in viral-driven cancer Adoptive cell transfer harnesses a patient's own T cells to destroy cancer. The strategy can successfully treat epithelial tumors driven by human papillomavirus (HPV), but it remains unclear why only some patients respond. Stevanović et al. examined the antitumor T cell response associated with HPV+ cervical cancers that underwent complete regression. Unexpectedly, reactive T cells were not directed against virally associated antigens, but rather against cancer germline antigens or neoantigens not previously recognized by the immune system. These findings counter the widely held belief that T cell responses against viral antigens are responsible for therapeutic effects in HPV-driven cancers. Science, this issue p. 200 Reactive T cells directed against nonviral antigens lead to regression of human papilloma virus–positive cervical cancer. Immunotherapy has clinical activity in certain virally associated cancers. However, the tumor antigens targeted in successful treatments remain poorly defined. We used a personalized immunogenomic approach to elucidate the global landscape of antitumor T cell responses in complete regression of human papillomavirus–associated metastatic cervical cancer after tumor-infiltrating adoptive T cell therapy. Remarkably, immunodominant T cell reactivities were directed against mutated neoantigens or a cancer germline antigen, rather than canonical viral antigens. T cells targeting viral tumor antigens did not display preferential in vivo expansion. Both viral and nonviral tumor antigen–specific T cells resided predominantly in the programmed cell death 1 (PD-1)–expressing T cell compartment, which suggests that PD-1 blockade may unleash diverse antitumor T cell reactivities. These findings suggest a new paradigm of targeting nonviral antigens in immunotherapy of virally associated cancers.

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免疫原性肿瘤抗原在病毒诱导的上皮癌成功免疫治疗中的格局

在病毒驱动的癌症中靶向非病毒抗原 过继细胞转移利用患者自身的 T 细胞来摧毁癌症。该策略可以成功治疗由人乳头瘤病毒 (HPV) 驱动的上皮肿瘤，但尚不清楚为什么只有一些患者有反应。斯特凡诺维奇等人。检查了与经历完全消退的 HPV+ 宫颈癌相关的抗肿瘤 T 细胞反应。出乎意料的是，反应性 T 细胞不是针对病毒相关抗原，而是针对癌症种系抗原或以前未被免疫系统识别的新抗原。这些发现反驳了广泛接受的观点，即 T 细胞对病毒抗原的反应是 HPV 驱动癌症治疗效果的原因。科学，这个问题 p。200 针对非病毒抗原的反应性 T 细胞导致人乳头瘤病毒阳性宫颈癌的消退。免疫疗法在某些病毒相关癌症中具有临床活性。然而，成功治疗中靶向的肿瘤抗原仍然不明确。我们使用个性化的免疫基因组学方法来阐明肿瘤浸润过继 T 细胞治疗后人乳头瘤病毒相关转移性宫颈癌完全消退的抗肿瘤 T 细胞反应的全球格局。值得注意的是，免疫显性 T 细胞的反应性是针对突变的新抗原或癌症种系抗原，而不是典型的病毒抗原。靶向病毒肿瘤抗原的 T 细胞没有表现出优先的体内扩增。病毒和非病毒肿瘤抗原特异性 T 细胞主要存在于表达程序性细胞死亡 1 (PD-1) 的 T 细胞区室中，这表明阻断 PD-1 可能会释放多种抗肿瘤 T 细胞反应性。这些发现表明在病毒相关癌症的免疫治疗中靶向非病毒抗原的新范式。