美国阿斯利康公司Dmitry I. Gabrilovich研究组发现肿瘤微环境中的过氧亚硝酸盐(PNT)改变抗原的形态，使其从癌症免疫治疗中逃逸。这一研究成果发表在2022年10月10日出版的国际学术期刊《癌细胞》上。

他们证明PNT改变了肿瘤细胞上呈现的MHC I类结合肽的结构。只有针对PNT耐药肽的CTL在体内具有很强的抗肿瘤作用，而针对PNT敏感肽的细胞毒性T淋巴细胞(CTLs)则没有效果。PNT在小鼠中的治疗靶向性降低了肿瘤细胞对CTL的耐药性。肿瘤中PNT活性低的黑色素瘤患者对免疫治疗的临床反应优于PNT活性高的患者。他们的数据表明，在设计以新抗原为基础的治疗时，应考虑肿瘤内PNT活性，也可能是一个重要的免疫治疗靶点。

据悉，癌症免疫治疗往往依赖于CTL对肽表位的识别。肿瘤微环境(TME)因PNT而富集，PNT是浸润髓细胞和一些肿瘤细胞产生的一种强效氧化剂。

附：英文原文

Title: Peroxynitrite in the tumor microenvironment changes the profile of antigens allowing escape from cancer immunotherapy

Author: Evgenii N. Tcyganov, Emilio Sanseviero, Douglas Marvel, Thomas Beer, Hsin-Yao Tang, Peter Hembach, David W. Speicher, Qianfei Zhang, Laxminarasimha R. Donthireddy, Ali Mostafa, Sabina Tsyganova, Vladimir Pisarev, Terri Laufer, Dmitriy Ignatov, Soldano Ferrone, Christiane Meyer, Hélène Maby-El Hajjami, Daniel E. Speiser, Sooner Altiok, Scott Antonia, Xiaowei Xu, Wei Xu, Cathy Zheng, Lynn M. Schuchter, Ravi K. Amaravadi, Tara C. Mitchell, Giorgos C. Karakousis, Zhe Yuan, Luis J. Montaner, Esteban Celis, Dmitry I. Gabrilovich

Issue&Volume: 2022/10/10

Abstract: Cancer immunotherapy often depends on recognition of peptide epitopes by cytotoxicT lymphocytes (CTLs). The tumor microenvironment (TME) is enriched for peroxynitrite(PNT), a potent oxidant produced by infiltrating myeloid cells and some tumor cells.We demonstrate that PNT alters the profile of MHC class I bound peptides presentedon tumor cells. Only CTLs specific for PNT-resistant peptides have a strong antitumoreffect in vivo, whereas CTLs specific for PNT-sensitive peptides are not effective. Therapeutictargeting of PNT in mice reduces resistance of tumor cells to CTLs. Melanoma patientswith low PNT activity in their tumors demonstrate a better clinical response to immunotherapythan patients with high PNT activity. Our data suggest that intratumoral PNT activityshould be considered for the design of neoantigen-based therapy and also may be animportant immunotherapeutic target.

DOI: 10.1016/j.ccell.2022.09.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00393-2