HPV16 RNA-LPX vaccine mediates complete regression of aggressively growing HPV-positive mouse tumors and establishes protective T cell memory
HPV16 RNA-LPX vaccine mediates complete regression of aggressively growing HPV-positive mouse tumors and establishes protective T cell memory
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DOI：
10.1080/2162402x.2019.1629259
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发表时间：
2019-07-12
期刊：
影响因子：
7.2
通讯作者：
Sahin, Ugur
中科院分区：
文献类型：
--
作者：
Grunwitz, Christian;Salomon, Nadja;Sahin, Ugur
HPV 16感染与多种癌症相关，并且有令人信服的证据表明HPV 16的转化活性关键取决于病毒癌蛋白E6和E7的表达。能够产生针对这些HPV 16抗原的持久和特异性免疫的治疗性癌症疫苗在实现长期疾病控制方面具有很大的希望。在这里，我们在小鼠中显示，HPV 16 E7 RNA-LPX，一种基于免疫组织化学优化的抗原编码mRNA的静脉注射癌症疫苗，有效地引发和扩增抗原特异性效应和记忆CD 8（+）T细胞。免疫小鼠的HPV阳性TC-1和C3肿瘤被活化的免疫细胞和HPV 16特异性T细胞严重浸润，并向促炎性、细胞毒性和较低免疫抑制性环境极化。E7 RNA-LPX免疫介导进展性肿瘤的完全和持久缓解。循环记忆T细胞具有高度细胞毒性，并可防止肿瘤再攻击。此外，E7 RNA-LPX免疫使抗PD-L1难治性肿瘤对检查点阻断敏感。总之，我们的数据突出了HPV 16 RNA-LPX治疗HPV驱动的癌症的潜力。
HPV16 infections are associated with a variety of cancers and there is compelling evidence that the transforming activity of HPV16 critically depends on the expression of the viral oncoproteins E6 and E7. Therapeutic cancer vaccines capable of generating durable and specific immunity against these HPV16 antigens hold great promise to achieve long-term disease control. Here we show in mice that HPV16 E7 RNA-LPX, an intravenously administered cancer vaccine based on immuno-pharmacologically optimized antigen-encoding mRNA, efficiently primes and expands antigen-specific effector and memory CD8(+) T cells. HPV-positive TC-1 and C3 tumors of immunized mice are heavily infiltrated with activated immune cells and HPV16-specific T cells and are polarized towards a proinflammatory, cytotoxic and less immune-suppressive contexture. E7 RNA-LPX immunization mediates complete and durable remission of progressing tumors. Circulating memory T cells are highly cytotoxic and protect from tumor rechallenge. Moreover, E7 RNA-LPX immunization sensitizes anti-PD-L1 refractory tumors to checkpoint blockade. In conclusion, our data highlight the potential of HPV16 RNA-LPX for the treatment of HPV-driven cancers.