The Role of ICOSL Signalling in Programming TAMs in PDA and Cancer Immunotherapy

ICOSL 信号转导在 PDA 和癌症免疫治疗中 TAM 编程中的作用

• 批准号: 466663503
• 负责人: Dr. Daniel Weissinger
• 金额: --
• 依托单位: Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/466663503?language=en
• 关键词: Role; ICOSL; Signalling; Programming; TAMs

Pancreatic ductal adenocarcinoma (PDA) is a devastating disease with a five-year overall survival rate of 9% and an increasing incidence rate in germany. PDA is associated with a modest T cell infiltrate, whose terminal differentiation status can have divergent effects on disease outcome by either combating cancer growth via antigen-specific tumoricidal immune responses or by promoting tumor-progression via the induction of immune-suppression. In particular, cytotoxic CD8+ T cells and Th1-polarized CD4+ T cells mediate protection against tumor development and are associated with prolonged survival in human PDA. Conversely, Th2- and Treg-polarized CD4+ T cells induce tumor-permissive tolerance. Unfortunately, directly targeting T cells or their checkpoint or costimulatory receptors has failed as an immunotherapeutic strategy in PDA as a result of T cell scarcity and their baseline low expression of checkpoint and costimulatory receptors. My mentor´s previous work suggests that T-cell infiltration and programming in PDA is largely dictated by two distinct phenotypes of tumor-associated macrophages (TAMs): M1-like TAMs which promote immunogenic T cell differentiation and, more often, M2-like TAMs which generate tumor permissive Th2 cells and Tregs. Therefore, a promising immunotherapeutic approach in PDA – rather than directly targeting T cells – is to reprogram TAMs towards an immunogenic M1-like anti-tumor phenotype. However, regulation of the balance between immunogenic and immune-suppressive TAM programming is uncertain and requires further exploration. ICOS is a well-studied costimulatory molecule that is primarily expressed on CD4+ T cells and whose ligation accentuates immunogenic responses. ICOSL is expressed on innate immune cells, most prominently macrophages. ICOSL possesses a short 23 amino acid cytoplasmic tail with a single tyrosine residue that is conserved in both humans and mice. While ICOS signaling is well-characterized, the concept of ICOSL ‘back-signaling’ in macrophages upon engagement by ICOS or other potential binding partners has not been explored. Preliminary work indicates that deletion or neutralization of ICOSL in TAMs results in their differentiation toward an alternatively activated CD206+IL10+ M2-like phenotype. By contrast, ICOSL engagement in TAMs leads to immunogenic differentiation into a MHCIIhighTNFα+ M1-like phenotype. Further ICOSL activation of TAMs confers tumor suppressive immunity in preliminary experiments. Based on these data, we postulate that ICOSL is a master regulator of macrophage programming and agonizing ICOSL will be an attractive avenue for immunotherapy in PDA. We expect to find that directly agonizing ICOSL in vivo or employing cellular therapy with ICOSL-activated macrophages will each be effective in immunotherapy of PDA and will activate the T cell compartment to enable efficacy for checkpoint-based immunotherapy.

胰腺导管腺癌（PDA）是一种毁灭性的疾病，五年总生存率为9%，在德国的发病率呈上升趋势。PDA与适度的T细胞浸润相关，其终末分化状态可以通过经由抗原特异性杀肿瘤免疫应答对抗癌症生长或通过经由诱导免疫抑制促进肿瘤进展而对疾病结果具有不同的影响。特别是，细胞毒性CD 8 + T细胞和Th 1-极化的CD 4 + T细胞介导对肿瘤发展的保护，并与人PDA的延长生存期相关。相反，Th 2和Treg极化的CD 4 + T细胞诱导肿瘤容许耐受。不幸的是，直接靶向T细胞或其检查点或共刺激受体作为PDA中的免疫抑制策略失败，这是由于T细胞稀缺及其检查点和共刺激受体的基线低表达。我的导师以前的工作表明，PDA中的T细胞浸润和编程在很大程度上取决于肿瘤相关巨噬细胞（TAM）的两种不同表型：促进免疫原性T细胞分化的M1样TAM，以及更常见的M2样TAM，它们产生肿瘤容许的Th 2细胞和Th 2细胞。因此，PDA中一种有前途的免疫治疗方法-而不是直接靶向T细胞-是将TAM重编程为免疫原性M1样抗肿瘤表型。然而，免疫原性和免疫抑制性TAM编程之间的平衡的调节是不确定的，需要进一步探索。ICOS是一种被充分研究的共刺激分子，其主要表达于CD 4 + T细胞上，并且其连接增强免疫原性应答。ICOSL在先天免疫细胞上表达，最显著的是巨噬细胞。ICOSL具有一个短的23个氨基酸的胞质尾区，其中有一个酪氨酸残基，在人和小鼠中均为保守残基。虽然ICOS信号传导被很好地表征，但在巨噬细胞中通过ICOS或其他潜在结合配偶体参与的ICOSL“反向信号传导”的概念尚未被探索。初步研究表明，TAM中ICOSL的缺失或中和导致它们向交替活化的CD 206 + IL 10 + M2样表型分化。相比之下，TAM中的ICOSL参与导致免疫原性分化为MHCI高TNF α+ M1样表型。在初步实验中，TAM的进一步ICOSL活化赋予肿瘤抑制性免疫。基于这些数据，我们假设ICOSL是巨噬细胞编程的主要调节剂，激动ICOSL将是PDA免疫治疗的一个有吸引力的途径。我们期望发现，在体内直接激动ICOL或采用ICOL活化的巨噬细胞的细胞疗法将各自在PDA的免疫疗法中有效，并且将激活T细胞区室以实现基于检查点的免疫疗法的功效。