Aging-associated and CD4 T-cell-dependent ectopic CXCL13 activation predisposes to anti-PD-1 therapy-induced adverse events.
Aging-associated and CD4 T-cell-dependent ectopic CXCL13 activation predisposes to anti-PD-1 therapy-induced adverse events.
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DOI：
10.1073/pnas.2205378119
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发表时间：
2022-07-19
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
免疫检查点阻断（包括抗程序性死亡受体（PD）-1治疗）诱导的免疫相关不良事件（irAE）是癌症免疫治疗中的一个主要问题。更多生理发生irAE的临床前模型可能有助于阐明irAE的根本原因和自然发展过程。在这里，我们发现在荷瘤的老年小鼠中，而不是年轻小鼠中，单独的抗PD-（L）1治疗通过CD 4 T细胞衍生的白细胞介素（IL）-21和随后的年龄特异性CXCL 13在三级淋巴结构中的表达诱导irAE样多器官毒性。与该动物模型一致，CXCL 13的全身性增加与癌症患者中的irAE发病率相关。这些发现为irAE管理策略的开发提供了深入见解，该策略平衡了irAE相关的免疫应答和抗肿瘤免疫监视。免疫检查点阻断（ICB）癌症免疫治疗的临床成功受到免疫相关不良事件（irAE）风险增加的影响。然而，irAE发生的免疫应答机制尚未完全探索。在此，我们发现，在荷瘤的老年小鼠中，抗程序性死亡受体（PD）-1治疗引起irAE样多器官功能障碍，在受损器官中异位积累T和B细胞。在该临床前模型中，器官毒性是由免疫球蛋白G（IgG）沉积介导的，因为从ICB处理的老年小鼠中给予IG诱导了特异性在幼稚老年宿主中的致病性。从机制上讲，CD 4 T细胞衍生的白细胞介素（IL）-21上调B细胞归巢趋化因子CXCL 13，优先在抗PD-1治疗的老年小鼠的irAE器官中。ICB诱导的致病性通过B细胞耗竭或通过阻断IL-21或CXCL 13活性而减轻。这些结果表明，年龄相关的免疫调节环境有助于在irAE器官中形成三级淋巴样结构的淋巴细胞聚集体和使用IL-21-CXCL 13-自身抗体轴的irAE相关毒性。支持这一点，在ICB治疗的患者中，CD 4 T细胞中CXCL 13和IL 21表达的全身性增加与irAE发生率相关。这些发现为CXCL 13在irAE管理中的治疗有效性提供了理论基础。
Immune-related adverse events (irAEs) induced by immune-checkpoint blockade including antiprogrammed death receptor (PD)-1 therapy are a major problematic issue in cancer immunotherapy. Preclinical models for more physiologically occurring irAEs are potentially useful for the clarification of fundamental causes and natural developmental course of irAEs. Here, we found that in tumor-bearing aged, but not young, mice, anti–PD-(L)1 therapy alone induces irAE-like multiorgan toxicities through CD4 T-cell–derived interleukin (IL)-21 and subsequent age-specific CXCL13 expression in tertiary lymphoid structure. Consistent with this animal model, a systemic increase in CXCL13 correlates with irAE incidence in cancer patients. These findings provide insight into the development of management strategies for irAE that balance both irAE-related immune response and antitumor immune surveillance. Clinical success of immune-checkpoint blockade (ICB) cancer immunotherapy is compromised by increased risk of immune-related adverse events (irAEs). However, mechanistic action(s) of immune responses underlying development of irAE remain not fully explored. Here, we found that in tumor-bearing aged, but not young, mice, antiprogrammed death receptor (PD)-1 therapy elicited irAE-like multiorgan dysfunctions with ectopic accumulation of T and B cells in damaged organs. In this preclinical model, the organ toxicities were mediated by immunoglobulin G (IgG) deposition because administration of IG from ICB-treated aged mice induced the pathogenicity specifically in naïve aged hosts. Mechanistically, CD4 T-cell–derived interleukin (IL)-21 upregulated B-cell–homing chemokine, CXCL13, preferentially in irAE organs from aged mice treated with anti–PD-1 therapy. The ICB-induced pathogenicity was alleviated by B-cell depletion or by blockade of IL-21 or CXCL13 activity. These results suggest that age-associated immune regulatory milieu contributes to the formation of tertiary lymphoid structure-like lymphocytic aggregates in irAE organs and irAE-related toxicity employing IL-21-CXCL13-auto-antibody axis. Supporting this, a systemic increase in CXCL13 and Il21 expression in CD4 T cells correlated with irAE incidence in ICB-treated patients. These findings provide rationale for therapeutic usefulness of CXCL13 in irAE management.
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DOI：
10.1084/jem.20141380
发表时间：
2015-04-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hatzi K;Nance JP;Kroenke MA;Bothwell M;Haddad EK;Melnick A;Crotty S
通讯作者：
Crotty S
影响因子：
10
作者：
Moazed F;Burnham EL;Vandivier RW;O'Kane CM;Shyamsundar M;Hamid U;Abbott J;Thickett DR;Matthay MA;McAuley DF;Calfee CS
通讯作者：
Calfee CS
影响因子：
64.8
作者：
Cabrita, Rita;Lauss, Martin;Jonsson, Goran
通讯作者：
Jonsson, Goran
DOI：
10.1073/pnas.1416498111
发表时间：
2014-10-14
影响因子：
11.1
作者：
Ammirante, Massimo;Shalapour, Shabnam;Karin, Michael
通讯作者：
Karin, Michael
影响因子：
17.1
作者：
Goswami, Sangeeta;Chen, Yulong;Sharma, Padmanee
通讯作者：
Sharma, Padmanee