Intratumoral injection of schwannoma with attenuated Salmonella typhimurium induces antitumor immunity and controls tumor growth.
Intratumoral injection of schwannoma with attenuated Salmonella typhimurium induces antitumor immunity and controls tumor growth.
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DOI：
10.1073/pnas.2202719119
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发表时间：
2022-06-14
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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2型神经纤维瘤病（NF 2）是由生长缓慢的良性神经鞘瘤引起的，这些神经鞘瘤在全身发展并导致严重的疼痛、发病率和死亡率。手术切除和放射治疗是NF 2的标准治疗方法，但有很大的局限性。NF 2治疗选择的缺乏是一个主要的未满足的医疗需求。在这里，我们表明，使用减毒鼠伤寒沙门氏菌菌株的细菌疗法免疫疗法可以控制这种肿瘤在临床前小鼠模型。这种策略减少了血管生成和注射肿瘤的体积，并诱导了全身免疫应答以及靶向远端肿瘤并防止新病变发展的免疫记忆应答。这些结果支持减毒S.鼠伤寒沙门氏菌作为NF 2疾病的治疗。神经鞘瘤是一种生长缓慢的良性肿瘤，在全身发展，引起疼痛、感觉/运动功能障碍和死亡。由于细菌免疫疗法已被用于治疗一些恶性肿瘤，我们评估减毒鼠伤寒沙门氏菌菌株作为良性小鼠神经鞘瘤的免疫疗法。测试了几种细菌菌株，包括VNP 20009，一种高度减毒的菌株，先前在患有晚期恶性肿瘤的人类受试者中显示是安全的，以及VNP 20009突变体，其在运动性和其他特性（包括对培养的哺乳动物细胞的粘附和侵袭）方面发生了改变。VNP 20009控制了两种鼠神经鞘瘤模型中的肿瘤生长，并诱导了细胞因子和免疫效应细胞谱的变化，与对照相比，这些变化与诱导增强的先天性和适应性宿主免疫应答一致。瘤内（i.t.）注射S.鼠伤寒沙门氏菌导致肿瘤细胞凋亡、肿瘤血管生成减少和注射的神经鞘瘤肿瘤的生长降低。侵袭性VNP 20009在控制注射肿瘤的生长方面比非侵袭性衍生物显著更有效。细菌治疗明显诱导全身抗肿瘤免疫，因为初次细菌治疗后植入的再激发神经鞘瘤的生长也减少了。通过全身施用抗PD-1抗体诱导的检查点程序性死亡-1（PD-1）阻断将肿瘤生长控制到与i.t.注射S.鼠伤寒沙门氏菌，并且这两种疗法一起对抑制神经鞘瘤生长具有相加作用。这些实验代表了良性肿瘤的细菌治疗的有效性，并支持S。鼠伤寒沙门氏菌VNP 20009，潜在地与PD-1抑制组合，作为神经鞘瘤免疫疗法。
Neurofibromatosis type 2 (NF2) is caused by slow-growing benign schwannomas that develop throughout the body and cause severe pain, morbidity, and mortality. Surgical resection and radiotherapy are the standards of care for NF2 but have major limitations. The paucity of NF2 therapeutic options is a major unmet medical need. Here, we show that bacteriotherapy immunotherapy using an attenuated strain of Salmonella typhimurium can control this neoplasm in a preclinical mouse model. This strategy decreased angiogenesis and the volume of the injected tumor and induced a systemic immune response as well as an immunological memory response that targeted distal tumors and prevented development of new lesions. These results support the evaluation of attenuated S. typhimurium as a treatment for NF2 disease. Schwannomas are slow-growing benign neoplasms that develop throughout the body causing pain, sensory/motor dysfunction, and death. Because bacterial immunotherapy has been used in the treatment of some malignant neoplasms, we evaluated attenuated Salmonella typhimurium strains as immunotherapies for benign murine schwannomas. Several bacterial strains were tested, including VNP20009, a highly attenuated strain that was previously shown to be safe in human subjects with advanced malignant neoplasms, and a VNP20009 mutant that was altered in motility and other properties that included adherence and invasion of cultured mammalian cells. VNP20009 controlled tumor growth in two murine schwannoma models and induced changes in cytokine and immune effector cell profiles that were consistent with induction of enhanced innate and adaptive host immune responses compared with controls. Intratumoral (i.t.) injection of S. typhimurium led to tumor cell apoptosis, decreased tumor angiogenesis, and lower growth of the injected schwannoma tumors. Invasive VNP20009 was significantly more efficacious than was a noninvasive derivative in controlling the growth of injected tumors. Bacterial treatment apparently induced systemic antitumor immunity in that the growth of rechallenge schwannomas implanted following primary bacterial treatment was also reduced. Checkpoint programmed death-1 (PD-1) blockade induced by systemic administration of anti–PD-1 antibodies controlled tumor growth to the same degree as i.t. injection of S. typhimurium, and together, these two therapies had an additive effect on suppressing schwannoma growth. These experiments represent validation of a bacterial therapy for a benign neoplasm and support development of S. typhimurium VNP20009, potentially in combination with PD-1 inhibition, as a schwannoma immunotherapy.
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影响因子：
17.1
作者：
Gurbatri CR;Lia I;Vincent R;Coker C;Castro S;Treuting PM;Hinchliffe TE;Arpaia N;Danino T
通讯作者：
Danino T
影响因子：
2
作者：
Kiyuna, Tasuku;Tome, Yasunori;Hoffman, Robert M.
通讯作者：
Hoffman, Robert M.
影响因子：
5.5
作者：
Bierschenk, Damien;Monteleone, Mercedes;Schroder, Kate
通讯作者：
Schroder, Kate
DOI：
10.1016/b978-0-444-52891-9.00039-7
发表时间：
2013-01-01
期刊：
PEDIATRIC NEUROLOGY, PT I
影响因子：
--
作者：
Korf, Bruce R.
通讯作者：
Korf, Bruce R.
DOI：
10.4049/jimmunol.2000382
发表时间：
2021-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gram AM;Wright JA;Pickering RJ;Lam NL;Booty LM;Webster SJ;Bryant CE
通讯作者：
Bryant CE