Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110.
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108.
Proc Natl Acad Sci U S A. 2021 Jun 15;118(24). doi: 10.1073/pnas.2102611118.
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 Kras 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.
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获益，因此找到能够拓宽应答患者群体的机制非常重要。一般来说，具有高突变负担的肿瘤有可能表达更多数量的突变型新抗原。由于新抗原可以作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的反应更好。鉴于外照射 1) 是癌症治疗的标准疗法，2) 诱导治疗细胞中突变蛋白和潜在突变新抗原的表达，并且 3) 已显示与免疫检查点治疗 (ICT) 具有临床协同作用，我们假设这种协同作用的至少一种机制是在辐照细胞中产生新的突变型新抗原靶标。在此，我们使用 Kras x p53 肉瘤细胞系 (KP 肉瘤)，我们和其他人已经表明这些细胞系几乎没有突变，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，在体外接受 4 或 9 Gy 的单次照射后，KP 肉瘤细胞获得突变新抗原，并以依赖于 T 细胞的方式在体内对 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 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 肉瘤系易受 ICT 影响。这些结果提供了一个概念验证，即在辐照肿瘤细胞中诱导新的抗原靶标代表了一种额外的机制，可以解释放射治疗和免疫治疗协同作用的临床发现。
