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

胰腺导管腺癌（PDA）是一种毁灭性的疾病，5年总生存率为9%，在德国发病率不断上升。PDA与适度的T细胞浸润有关，其最终分化状态可以通过抗原特异性肿瘤杀伤免疫反应对抗癌症生长或通过诱导免疫抑制促进肿瘤进展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CD4+ T细胞介导对肿瘤发展的保护，并与人类PDA的延长存活有关。相反，Th2和treg极化的CD4+ T细胞诱导肿瘤容许性耐受。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的免疫治疗策略已经失败，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。我的导师之前的工作表明，T细胞在PDA中的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：m1样的tam促进免疫原性T细胞分化，更常见的是m2样的tam产生肿瘤许可的Th2细胞和Tregs。因此，一种有前景的PDA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编程之间的平衡调节尚不确定，需要进一步探索。ICOS是一种被充分研究的共刺激分子，主要在CD4+ T细胞上表达，其结扎可增强免疫原性反应。ICOSL在先天免疫细胞，尤其是巨噬细胞上表达。ICOSL具有一个短的23个氨基酸的细胞质尾部和一个酪氨酸残基，在人和小鼠中都是保守的。虽然ICOS信号已被很好地表征，但ICOSL在巨噬细胞中被ICOS或其他潜在结合伙伴参与后的“反向信号传导”概念尚未被探索。初步研究表明，TAMs中ICOSL的缺失或中和会导致其分化为CD206+IL10+ m2样表型。相比之下，ICOSL参与tam导致免疫原性分化为MHCIIhighTNFα+ m1样表型。在初步实验中，进一步激活ICOSL的tam赋予肿瘤抑制免疫。基于这些数据，我们假设ICOSL是巨噬细胞编程的主要调节因子，并且痛苦ICOSL将成为PDA免疫治疗的一个有吸引力的途径。我们希望发现，在体内直接使ICOSL痛苦或使用ICOSL活化的巨噬细胞进行细胞治疗，都能有效地用于PDA的免疫治疗，并激活T细胞室，从而使基于检查点的免疫治疗有效。

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.