The Role of ICOSL Signalling in Programming TAMs in PDA and Cancer Immunotherapy
Final Report Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with a fiveyear overall survival rate of approximately 11%. Moreover, it is projected to become the second leading cause of cancer-related deaths in western nations, like the United States, by 2030. Though a deadly disease, treatment options remain limited. Less than a quarter of all patients diagnosed with PDAC qualify for upfront surgery with curative intent, while the majority of patients are diagnosed with locally advanced or metastasised PDAC. Almost all patients receive chemotherapy as part of their treatment but not only are treatment options scarce but also limited in their efficiency. The emergence of immunotherapy as a new way to treat cancer shows promising results in multiple cancer types but has yet to show promising results in PDAC. The reasons for resistance to immunotherapy remain largely unknown. Therefore, a deeper understanding of PDAC, it’s Tumor micro-environment (TME) and the cellular interactions is critical for improving therapy and thereby improving clinical outcomes. While recent genomic and transcriptomic analyses have uncovered key molecular drivers and cancer subtypes these findings still lack a deeper understanding on the cellular level and have not yet manifested in clinical advances to treat PDAC. Single-cell RNA sequencing (scRNA-seq) is a promising tool to uncover cellular changes and enables in-depth characterisation of the TME. For a comprehensive understanding of the PDAC TME in treatment naive and chemotherapy-treated samples we collected freshly resected or biopsied tumour specimens from 27 patients and performed scRNA-seq. By this analysis we were able to characterise tumour cells and cells of the TME (immune cells and stromal cells) on a single cell level. This enabled a deeper understanding of the heterogeneity in each tumour and cellular interactions between cancer and TME cells. By RNA expression profiling we were able to identify significant heterogeneity in the malignant epithelial compartment, wherein most tumours show a variety of different PDAC cancer cell subtypes (basal-like and classical-like). Further identifying and characterising cells within the TME we examined different cancer-associated fibroblast populations (CAFs) with distinct features and similarly tumour-associated macrophages (TAMs) as well as T cells. By comparison of naive and chemotherapy-treated samples we further understood how chemotherapy alters the PDAC TME and might induces changes consistent with tumour progression and refractoriness to immunotherapy by downregulation of inhibitory checkpoint molecules in CD8 + T cells. We further identified TIGIT as a major checkpoint molecule that might offer a new therapeutic approach for a subset of PDAC patients.
Publications
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Abstract PR010: Single-cell sequencing elucidates the effects of chemotherapy on cancer cell heterogeneity and the tumor microenvironment of human pancreatic adenocarcinoma. Cancer Research, 82(22_Supplement), PR010-PR010.
Weissinger, Daniel; Kawaler, Emily A.; Werba, Gregor; Zhao, Ende; Kalfakakou, Despoina; Dhara, Surajit; Oh, Grace; Jing, Xiaohong; Beri, Nina; Khanna, Lauren; Gonda, Tamas; Oberstein, Paul E.; Hajdu, Cristina; Loomis, Cynthia; Heguy, Adriana; Sherman, Mara H.; Lund, Amanda W.; Welling, Theodore H.; Dolgalev, Igor ... & Simeone, Diane M.
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Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment. Nature Communications, 14(1).
Werba, Gregor; Weissinger, Daniel; Kawaler, Emily A.; Zhao, Ende; Kalfakakou, Despoina; Dhara, Surajit; Wang, Lidong; Lim, Heather B.; Oh, Grace; Jing, Xiaohong; Beri, Nina; Khanna, Lauren; Gonda, Tamas; Oberstein, Paul; Hajdu, Cristina; Loomis, Cynthia; Heguy, Adriana; Sherman, Mara H.; Lund, Amanda W. ... & Simeone, Diane M.
