Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity
Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity
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DOI：
10.1038/mt.2016.121
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发表时间：
2016-08-01
影响因子：
12.4
通讯作者：
Snyder, Christopher M.
中科院分区：
文献类型：
--
作者：
Erkes, Dan A.;Xu, Guangwu;Snyder, Christopher M.
巨细胞病毒是一种有吸引力的癌症疫苗平台，因为它诱导强烈的功能性CD 8（+）T细胞应答，这些应答随着时间的推移而积累并迁移到大多数组织中。为了探索这一点，我们使用鼠巨细胞病毒表达修饰的gp 100黑色素瘤抗原。通过腹膜内和皮内途径的治疗性疫苗接种诱导肿瘤浸润gp 100特异性CD 8（+）T细胞，但对皮下病变的益处最小。与此相反，肿瘤内感染已形成的肿瘤结节以CD 8（+）T细胞依赖的方式极大地抑制了肿瘤生长并提高了总生存率，即使在先前感染鼠巨细胞病毒的小鼠中也是如此。虽然小鼠巨细胞病毒在体外可以感染并杀死B16 F0，但在体内感染仅限于肿瘤相关的巨噬细胞。令人惊讶的是，病毒中肿瘤抗原的存在仅略微增加了肿瘤内感染的功效，并且肿瘤中的肿瘤特异性CD 8（+）T细胞仍然功能失调。重要的是，将肿瘤内鼠巨细胞病毒感染与抗PD-L1治疗相结合具有协同作用，导致超过一半的小鼠的肿瘤清除，并随后保护其免受肿瘤攻击。因此，虽然基于鼠巨细胞病毒的疫苗对已建立的皮下肿瘤效果不佳，但肿瘤结节的直接感染意外地延迟了肿瘤生长，并与免疫检查点阻断协同作用，以促进肿瘤清除和长期保护。
Cytomegalovirus is an attractive cancer vaccine platform because it induces strong, functional CD8(+) T-cell responses that accumulate over time and migrate into most tissues. To explore this, we used murine cytomegalovirus expressing a modified gp100 melanoma antigen. Therapeutic vaccination by the intraperitoneal and intradermal routes induced tumor infiltrating gp100-specific CD8(+) T-cells, but provided minimal benefit for subcutaneous lesions. In contrast, intratumoral infection of established tumor nodules greatly inhibited tumor growth and improved overall survival in a CD8(+) T-cell-dependent manner, even in mice previously infected with murine cytomegalovirus. Although murine cytomegalovirus could infect and kill B16F0s in vitro, infection was restricted to tumor-associated macrophages in vivo. Surprisingly, the presence of a tumor antigen in the virus only slightly increased the efficacy of intratumoral infection and tumor-specific CD8(+) T-cells in the tumor remained dysfunctional. Importantly, combining -intratumoral murine cytomegalovirus infection with anti-PD-L1 therapy was synergistic, resulting in tumor clearance from over half of the mice and subsequent protection against tumor challenge. Thus, while a murine cytomegalovirus-based vaccine was poorly-effective against established subcutaneous tumors, direct infection of tumor nodules unexpectedly delayed tumor growth and synergized with immune checkpoint-blockade to promote tumor clearance and long-term protection.