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

• Applicant: Dr. Daniel Weissinger
• Subject Area: General and Visceral Surgery
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466663503

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.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. George Miller