Xiang Bo, Baybutt Trevor R, Berman-Booty Lisa, Magee Michael S, Waldman Scott A, Alexeev Vitali Y, Snook Adam E
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107.
Department of Discovery Toxicology, Bristol-Myers Squibb, Princeton, NJ 08543.
J Immunol. 2017 May 1;198(9):3507-3514. doi: 10.4049/jimmunol.1502672. Epub 2017 Mar 24.
Heterologous prime-boost immunization with plasmid DNA and viral vector vaccines is an emerging approach to elicit CD8 T cell-mediated immunity targeting pathogens and tumor Ags that is superior to either monotherapy. Yet, the mechanisms underlying the synergy of prime-boost strategies remain incompletely defined. In this study, we examine a DNA and adenovirus (Ad5) combination regimen targeting guanylyl cyclase C (GUCY2C), a receptor expressed by intestinal mucosa and universally expressed by metastatic colorectal cancer. DNA immunization efficacy was optimized by i.m. delivery via electroporation, yet it remained modest compared with Ad5. Sequential immunization with DNA and Ad5 produced superior antitumor efficacy associated with increased TCR avidity, whereas targeted disruption of TCR avidity enhancement eliminated GUCY2C-specific antitumor efficacy, without affecting responding T cell number or cytokine profile. Indeed, functional TCR avidity of responding GUCY2C-specific CD8 T cells induced by various prime or prime-boost regimens correlated with antitumor efficacy, whereas T cell number and cytokine profile were not. Importantly, although sequential immunization with DNA and Ad5 maximized antitumor efficacy through TCR avidity enhancement, it produced no autoimmunity, reflecting sequestration of GUCY2C to intestinal apical membranes and segregation of mucosal and systemic immunity. Together, TCR avidity enhancement may be leveraged by prime-boost immunization to improve GUCY2C-targeted colorectal cancer immunotherapeutic efficacy and patient outcomes without concomitant autoimmune toxicity.
用质粒DNA和病毒载体疫苗进行异源初免-加强免疫是一种新兴的方法，可引发针对病原体和肿瘤抗原的CD8 T细胞介导的免疫，这种方法优于单一疗法。然而，初免-加强策略协同作用的潜在机制仍未完全明确。在本研究中，我们研究了一种针对鸟苷酸环化酶C（GUCY2C）的DNA和腺病毒（Ad5）联合方案，GUCY2C是一种由肠黏膜表达且在转移性结直肠癌中普遍表达的受体。通过电穿孔经肌肉注射优化了DNA免疫效果，但与Ad5相比仍较为有限。DNA和Ad5序贯免疫产生了与TCR亲和力增加相关的卓越抗肿瘤效果，而靶向破坏TCR亲和力增强则消除了GUCY2C特异性抗肿瘤效果，同时不影响反应性T细胞数量或细胞因子谱。实际上，由各种初免或初免-加强方案诱导的反应性GUCY2C特异性CD8 T细胞的功能性TCR亲和力与抗肿瘤效果相关，而T细胞数量和细胞因子谱则不然。重要的是，尽管DNA和Ad5序贯免疫通过增强TCR亲和力使抗肿瘤效果最大化，但未产生自身免疫，这反映了GUCY2C被隔离在肠顶端膜以及黏膜免疫和全身免疫的分离。总之，初免-加强免疫可利用TCR亲和力增强来提高针对GUCY2C的结直肠癌免疫治疗效果和患者预后，而不会伴随自身免疫毒性。
