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Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads [Immunology and Inflammation]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2021-06-15 , DOI: 10.1073/pnas.2102611118
Danielle M. Lussier, Elise Alspach, Jeffrey P. Ward, Alexander P. Miceli, Daniele Runci, J. Michael White, Cedric Mpoy, Cora D. Arthur, Heather N. Kohlmiller, Tyler Jacks, Maxim N. Artyomov, Buck E. Rogers, Robert D. Schreiber

Immunotherapies are a promising advance in cancer treatment. However, because only a subset of cancer patients benefits from these treatments it is important to find mechanisms that will broaden the responding patient population. Generally, tumors with high mutational burdens have the potential to express greater numbers of mutant neoantigens. As neoantigens can be targets of protective adaptive immunity, highly mutated tumors are more responsive to immunotherapy. Given that external beam radiation 1) is a standard-of-care cancer therapy, 2) induces expression of mutant proteins and potentially mutant neoantigens in treated cells, and 3) has been shown to synergize clinically with immune checkpoint therapy (ICT), we hypothesized that at least one mechanism of this synergy was the generation of de novo mutant neoantigen targets in irradiated cells. Herein, we use KrasG12D x p53−/− sarcoma cell lines (KP sarcomas) that we and others have shown to be nearly devoid of mutations, are poorly antigenic, are not controlled by ICT, and do not induce a protective antitumor memory response. However, following one in vitro dose of 4- or 9-Gy irradiation, KP sarcoma cells acquire mutational neoantigens and become sensitive to ICT in vivo in a T cell-dependent manner. We further demonstrate that some of the radiation-induced mutations generate cytotoxic CD8+ T cell responses, are protective in a vaccine model, and are sufficient to make the parental KP sarcoma line susceptible to ICT. These results provide a proof of concept that induction of new antigenic targets in irradiated tumor cells represents an additional mechanism explaining the clinical findings of the synergy between radiation and immunotherapy.



中文翻译:

辐射诱导的新抗原拓宽了低突变负荷癌症的免疫治疗窗口 [免疫学和炎症]

免疫疗法是癌症治疗的一个有希望的进步。然而,由于只有一部分癌症患者从这些治疗中受益,因此找到能够扩大响应患者群体的机制非常重要。一般来说,具有高突变负荷的肿瘤有可能表达更多的突变新抗原。由于新抗原可以成为保护性适应性免疫的靶标,因此高度突变的肿瘤对免疫疗法更敏感。鉴于外照射辐射 1) 是一种标准的癌症治疗,2) 诱导治疗细胞中突变蛋白和潜在突变新抗原的表达,以及 3) 已被证明与免疫检查点治疗 (ICT) 在临床上具有协同作用,我们假设这种协同作用的至少一种机制是在受辐照细胞中产生从头突变的新抗原靶点。我们和其他人已经证明几乎没有突变的G12D x p53 -/-肉瘤细胞系(KP 肉瘤),抗原性差,不受 ICT 控制,并且不会诱导保护性抗肿瘤记忆反应。然而,在一次体外剂量的 4-Gy 或 9-Gy 照射后,KP 肉瘤细胞获得突变的新抗原并以 T 细胞依赖性方式在体内变得对 ICT 敏感。我们进一步证明,一些辐射诱导的突变会产生细胞毒性 CD8 +T 细胞反应在疫苗模型中具有保护作用,并且足以使亲本 KP 肉瘤系对 ICT 敏感。这些结果提供了概念证明,即在受照射的肿瘤细胞中诱导新的抗原靶点代表了解释放射和免疫疗法之间协同作用的临床发现的额外机制。

更新日期:2021-06-08
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