PDF(Pubmed)
Abstract：
TIGIT is a negative immune checkpoint receptor associated with T cell exhaustion in cancer and HIV. TIGIT upregulation in virus-specific CD8+ T cells and NK cells during HIV/SIV infection results in dysfunctional effector capabilities. In vitro studies targeting TIGIT on CD8+ T cells suggest TIGIT blockade as a viable strategy to restore SIV-specific T cell responses. Here, we extend these studies in vivo using TIGIT blockage in nonhuman primates in an effort to reverse T cell and NK cell exhaustion in the setting of SIV infection. We demonstrate that in vivo administration of a humanized anti-TIGIT monoclonal antibody (mAb) is well tolerated in both cynomolgus macaques and rhesus macaques. Despite sustained plasma concentrations of anti-TIGIT mAb, we observed no consistent improvement in NK or T cell cytolytic capacity. TIGIT blockade minimally enhanced T cell proliferation and virus-specific T cell responses in both magnitude and breadth though plasma viral loads in treated animals remained stable indicating that anti-TIGIT mAb treatment alone was insufficient to increase anti-SIV CD8+ T cell function. The enhancement of virus-specific T cell proliferative responses observed in vitro with single or dual blockade of TIGIT and/or PD-1 highlights TIGIT as a potential target to reverse T cell dysfunction. Our studies, however, reveal that targeting the TIGIT pathway alone may be insufficient in the setting of viremia and that combining immune checkpoint blockade with other immunotherapeutics may be a future path forward for improved viral control or elimination of HIV.IMPORTANCEUpregulation of the immune checkpoint receptor TIGIT is associated with HIV-mediated T cell dysfunction and correlates with HIV disease progression. Compelling evidence exists for targeting immune checkpoint receptor pathways that would potentially enhance immunity and refocus effector cell efforts toward viral clearance. In this report, we investigate TIGIT blockade as an immunotherapeutic approach to reverse immune exhaustion during chronic SIV/SHIV infection in a nonhuman primate model of HIV infection. We show that interfering with the TIGIT signaling axis alone is insufficient to improve viral control despite modest improvement in T cell immunity. Our data substantiate the use of targeting multiple immune checkpoint receptors to promote synergy and ultimately eliminate HIV-infected cells.
摘要：
TIGIT是与癌症和HIV中的T细胞耗尽相关的负免疫检查点受体。HIV/SIV感染期间病毒特异性CD8+T细胞和NK细胞中的TIGIT上调导致功能失调的效应能力。在CD8+T细胞上靶向TIGIT的体外研究表明TIGIT阻断是恢复SIV特异性T细胞应答的可行策略。这里,我们在非人灵长类动物中使用TIGIT阻断在体内扩展这些研究,以在SIV感染的情况下逆转T细胞和NK细胞耗竭.我们证明了人源化抗TIGIT单克隆抗体（mAb）的体内给药在食蟹猴和恒河猴中均具有良好的耐受性。尽管抗TIGITmAb的血浆浓度持续，我们没有观察到NK或T细胞溶细胞能力的持续改善。TIGIT阻断在量级和广度上最低限度地增强T细胞增殖和病毒特异性T细胞应答,尽管治疗动物的血浆病毒载量保持稳定,表明单独的抗TIGITmAb治疗不足以增加抗SIVCD8+T细胞功能。用TIGIT和/或PD-1的单一或双重阻断在体外观察到的病毒特异性T细胞增殖应答的增强突出了TIGIT作为逆转T细胞功能障碍的潜在靶标。我们的研究,然而,揭示在病毒血症的背景下,仅靶向TIGIT途径可能不足,并且将免疫检查点阻断与其他免疫治疗剂相结合可能是改善病毒控制或消除HIV的未来途径.免疫检查点受体TIGIT的表达与HIV介导的T细胞功能障碍相关，并与HIV疾病进展相关。针对免疫检查点受体途径存在令人信服的证据，这些途径可能会增强免疫力并将效应细胞的努力重新集中在病毒清除上。在这份报告中,我们研究了在HIV感染的非人类灵长类动物模型中,TIGIT阻断作为逆转慢性SIV/SHIV感染期间免疫耗竭的免疫治疗方法.我们表明，单独干扰TIGIT信号轴不足以改善病毒控制，尽管在T细胞免疫方面有适度改善。我们的数据证实了靶向多种免疫检查点受体以促进协同作用并最终消除HIV感染细胞的用途。
