PDF(Pubmed)
Abstract：
Intratumoral Tregs are key mediators of cancer immunotherapy resistance, including anti-programmed cell death (ligand) 1 [anti-PD-(L)1] immune checkpoint blockade (ICB). The mechanisms driving Treg infiltration into the tumor microenvironment (TME) and the consequence on CD8+ T cell exhaustion remain elusive. Here, we report that heat shock protein gp96 (also known as GRP94) was indispensable for Treg tumor infiltration, primarily through the roles of gp96 in chaperoning integrins. Among various gp96-dependent integrins, we found that only LFA-1 (αL integrin), and not αV, CD103 (αE), or β7 integrin, was required for Treg tumor homing. Loss of Treg infiltration into the TME by genetic deletion of gp96/LFA-1 potently induced rejection of tumors in multiple ICB-resistant murine cancer models in a CD8+ T cell-dependent manner, without loss of self-tolerance. Moreover, gp96 deletion impeded Treg activation primarily by suppressing IL-2/STAT5 signaling, which also contributed to tumor regression. By competing for intratumoral IL-2, Tregs prevented the activation of CD8+ tumor-infiltrating lymphocytes, drove thymocyte selection-associated high mobility group box protein (TOX) induction, and induced bona fide CD8+ T cell exhaustion. By contrast, Treg ablation led to striking CD8+ T cell activation without TOX induction, demonstrating clear uncoupling of the 2 processes. Our study reveals that the gp96/LFA-1 axis plays a fundamental role in Treg biology and suggests that Treg-specific gp96/LFA-1 targeting represents a valuable strategy for cancer immunotherapy without inflicting autoinflammatory conditions.
摘要：
肿瘤内调节性T细胞（Tregs）是癌症免疫治疗耐药的关键介质，包括抗PD-（L）1免疫检查点阻断（ICB）。驱动Treg浸润到肿瘤微环境(TME)中的机制和对CD8+T细胞耗尽的后果仍然难以捉摸。在这里，我们报道热休克蛋白gp96(GRP94)是Treg肿瘤浸润不可缺少的,主要通过gp96在陪伴整合素中的作用。在各种依赖gp96的整合素中，我们发现只有LFA-1(αL整合素)而不是αV，Treg肿瘤归巢需要CD103(αE)或β7整合素。通过基因删除gp96/LFA-1使Treg渗入TME中的损失以CD8+T细胞依赖性方式有效诱导多种ICB抗性鼠癌症模型的排斥,而不丧失自身耐受性。此外，gp96缺失主要通过抑制IL-2/STAT5信号传导来阻碍Treg激活，这也有助于肿瘤消退。通过竞争肿瘤内IL-2，Tregs阻止CD8+肿瘤浸润淋巴细胞（TIL）的激活，驱动TOX诱导并诱导真正的CD8+T细胞衰竭。相比之下,Treg消融导致CD8+T细胞激活而没有TOX诱导，证明了这两个过程的清晰解耦。我们的研究表明，gp96/LFA-1轴在Treg生物学中起着基本作用，并表明Treg特异性gp96/LFA-1靶向代表了一种有价值的癌症免疫治疗策略，而不会造成自身炎症。
