Radiation Augments the Local Anti-Tumor Effect of In Situ Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models.
Radiation Augments the Local Anti-Tumor Effect of In Situ Vaccine With CpG-Oligodeoxynucleotides and Anti-OX40 in Immunologically Cold Tumor Models.
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DOI：
10.3389/fimmu.2021.763888
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发表时间：
2021
影响因子：
7.3
通讯作者：
Morris ZS
中科院分区：
文献类型：
--
作者：
Pieper AA;Zangl LM;Speigelman DV;Feils AS;Hoefges A;Jagodinsky JC;Felder MA;Tsarovsky NW;Arthur IS;Brown RJ;Birstler J;Le T;Carlson PM;Bates AM;Hank JA;Rakhmilevich AL;Erbe AK;Sondel PM;Patel RB;Morris ZS
将 CpG 寡脱氧核苷酸与抗 OX40 激动剂抗体 (CpG+OX40) 组合能够在某些肿瘤模型（包括 A20 淋巴瘤模型）中产生有效的原位疫苗。免疫学“冷”肿瘤通常对免疫治疗反应较差，其特点是肿瘤浸润淋巴细胞 (TIL) 少、突变负荷低和新抗原表达有限。放射治疗（RT）可以改变免疫学“冷”肿瘤的肿瘤微环境（TME）。本研究研究了 RT 与原位疫苗 CpG+OX40 相结合在免疫“冷”肿瘤模型中的效果。采用局部 RT、CpG 和/或 OX40 组合治疗患有侧腹肿瘤（A20 淋巴瘤、B78 黑色素瘤或 4T1 乳腺癌）的小鼠，并监测对治疗的反应。进行流式细胞术和定量聚合酶链反应（qPCR）实验来研究治疗后 TME、次级淋巴器官和免疫激活的差异。 CpG+OX40 原位疫苗方案在 A20 模型中有效，但在“冷”B78 和 4T1 模型中并未显着改善肿瘤反应或存活率，如此处所测试。在这两种模型中，在 CpG+OX40 之前进行 RT 治疗能够对这种原位疫苗产生局部反应，与单独 RT 或单独 CpG+OX40 相比，显着提高抗肿瘤反应和生存率。 RT 增加肿瘤浸润 CD4+ 非调节性 T 细胞上 OX40 的表达。 RT+CpG+OX40 增加了肿瘤浸润效应 T 细胞与 T 调节细胞的比率，并显着增加了肿瘤引流淋巴结 (TDLN) 和脾脏中 CD4+ 和 CD8+ T 细胞的活化。 RT 显着提高了原位疫苗 CpG+OX40 在免疫学“冷”实体小鼠肿瘤模型中的局部抗肿瘤效果，其中单独使用 RT 或 CpG+OX40 无法刺激肿瘤消退。
Combining CpG oligodeoxynucleotides with anti-OX40 agonist antibody (CpG+OX40) is able to generate an effective in situ vaccine in some tumor models, including the A20 lymphoma model. Immunologically “cold” tumors, which are typically less responsive to immunotherapy, are characterized by few tumor infiltrating lymphocytes (TILs), low mutation burden, and limited neoantigen expression. Radiation therapy (RT) can change the tumor microenvironment (TME) of an immunologically “cold” tumor. This study investigated the effect of combining RT with the in situ vaccine CpG+OX40 in immunologically “cold” tumor models. Mice bearing flank tumors (A20 lymphoma, B78 melanoma or 4T1 breast cancer) were treated with combinations of local RT, CpG, and/or OX40, and response to treatment was monitored. Flow cytometry and quantitative polymerase chain reaction (qPCR) experiments were conducted to study differences in the TME, secondary lymphoid organs, and immune activation after treatment. An in situ vaccine regimen of CpG+OX40, which was effective in the A20 model, did not significantly improve tumor response or survival in the “cold” B78 and 4T1 models, as tested here. In both models, treatment with RT prior to CpG+OX40 enabled a local response to this in situ vaccine, significantly improving the anti-tumor response and survival compared to RT alone or CpG+OX40 alone. RT increased OX40 expression on tumor infiltrating CD4+ non-regulatory T cells. RT+CpG+OX40 increased the ratio of tumor-infiltrating effector T cells to T regulatory cells and significantly increased CD4+ and CD8+ T cell activation in the tumor draining lymph node (TDLN) and spleen. RT significantly improves the local anti-tumor effect of the in situ vaccine CpG+OX40 in immunologically “cold”, solid, murine tumor models where RT or CpG+OX40 alone fail to stimulate tumor regression.
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影响因子：
12.4
作者：
Jagodinsky JC;Jin WJ;Bates AM;Hernandez R;Grudzinski JJ;Marsh IR;Chakravarty I;Arthur IS;Zangl LM;Brown RJ;Nystuen EJ;Emma SE;Kerr C;Carlson PM;Sriramaneni RN;Engle JW;Aluicio-Sarduy E;Barnhart TE;Le T;Kim K;Bednarz BP;Weichert JP;Patel RB;Morris ZS
通讯作者：
Morris ZS
影响因子：
4.4
作者：
Buhtoiarov, IN;Lum, H;Rakhmilevich, AL
通讯作者：
Rakhmilevich, AL
影响因子：
4.4
作者：
Bansal-Pakala, P;Halteman, BS;Croft, M
通讯作者：
Croft, M
影响因子：
15.9
作者：
Marabelle, Aurelien;Kohrt, Holbrook;Levy, Ronald
通讯作者：
Levy, Ronald
DOI：
10.1084/jem.191.2.201
发表时间：
2000-01-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lane P
通讯作者：
Lane P