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

胰腺导管腺癌(PDA)是一种破坏性疾病，其五年总存活率为9%，在德国的发病率呈上升趋势。PDA与适度的T细胞浸润有关，其终末分化状态可通过抗原特异性杀瘤免疫反应抑制肿瘤生长或通过诱导免疫抑制促进肿瘤进展而对疾病结局产生不同的影响。特别是，细胞毒性CD8+T细胞和Th1极化的CD4+T细胞介导了对肿瘤发展的保护作用，并与人类PDA的存活时间延长有关。相反，Th2和Treg极化的CD4+T细胞诱导肿瘤耐受性。不幸的是，直接靶向T细胞或其检查点或共刺激受体作为一种免疫治疗策略在PDA中失败了，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S以前的工作表明，T细胞在PDA中的渗透和编程在很大程度上由两种不同的肿瘤相关巨噬细胞(TAM)决定：M1样TAM促进免疫原性T细胞分化，更常见的是M2样TAM产生肿瘤允许的Th2细胞和Tregs。因此，PDA的一种有前景的免疫治疗方法--而不是直接针对T细胞--是将TAMs重新编程为免疫原性M1样抗肿瘤表型。然而，对免疫原性和免疫抑制之间的平衡的调节是不确定的，需要进一步的探索。ICOS是一种研究广泛的共刺激分子，主要表达在CD4+T细胞上，其连接可增强免疫原性反应。ICOSL表达于先天免疫细胞，尤其是巨噬细胞。ICOSL有一个短小的23个氨基酸的细胞质尾巴，只有一个酪氨酸残基，这在人类和小鼠中都是保守的。虽然ICOS信号已被很好地描述，但ICOSL在巨噬细胞中与ICOS或其他潜在结合伙伴接触时的“反向信号”概念尚未被探索。初步工作表明，TAMS中ICOSL的缺失或中和导致其分化为CD206+IL10+M2样表型。相反，ICOSL参与TAMS导致免疫原性分化为MHCII高肿瘤坏死因子α+M1样表型。在初步实验中，进一步激活TAMS的ICOSL可提供肿瘤抑制免疫。基于这些数据，我们推测ICOSL是巨噬细胞编程的主要调节者，而痛苦的ICOSL将是PDA免疫治疗的一个有吸引力的途径。我们期望发现，在体内直接折磨ICOSL或使用ICOSL激活的巨噬细胞进行细胞治疗在PDA的免疫治疗中都是有效的，并将激活T细胞室以实现基于检查点的免疫治疗的疗效。

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.