Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads
Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads
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DOI：
10.1073/pnas.2102611118
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发表时间：
2021-06-15
影响因子：
11.1
通讯作者：
Schreiber，Robert D.
中科院分区：
文献类型：
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作者：
Lussier，Danielle M.;Alspach，Elise;Schreiber，Robert D.
免疫疗法是癌症治疗的一个有前途的进展。然而，由于只有一部分癌症患者从这些治疗中受益，因此重要的是要找到扩大响应患者群体的机制。通常，具有高突变负荷的肿瘤具有表达更多数量的突变新抗原的潜力。由于新抗原可以是保护性适应性免疫的靶点，因此高度突变的肿瘤对免疫疗法更敏感。鉴于外部射束辐射1）是护理癌症疗法的标准，2）诱导突变蛋白和潜在突变新抗原在经处理细胞中的表达，以及3）已显示与免疫检查点疗法（ICT）在临床上协同作用，我们假设这种协同作用的至少一种机制是在经辐照细胞中产生从头突变新抗原靶标。在本文中，我们使用KrasG 12 Dx p53−/−肉瘤细胞系（KP肉瘤），我们和其他人已经证明几乎没有突变，抗原性差，不受ICT控制，并且不诱导保护性抗肿瘤记忆反应。然而，在一次体外剂量的4-或9-戈伊照射后，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对ICT敏感。我们进一步证明，一些辐射诱导的突变产生细胞毒性CD 8 +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。这些结果提供了一个概念的证据，即在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另一种机制。
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 KrasG12Dx 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.