Pancreatic Adenocarcinoma (PDAC) is a highly lethal cancer with a 5-year survival rate of only 7%. Limited and ineffective treatment options are partially due to the intricate and undefined interactions within the tumour microenvironment (TME). Understanding the molecular pathology and oncogenesis of PDAC is crucial for improving patient outcomes and developing innovative therapies.
In a multinational effort, our group has previously performed large-scale genomic, transcriptomic, and epigenomic analyses of >1000 pancreatic adenocarcinomas, expanding the repertoire of driver mutations involved in this disease to more than 60. To further resolve intra-tumour heterogeneity, cellular composition, and cell-specific expression signatures, we integrated single-nucleus RNA and ATAC high-throughput sequencing, from the same sample preparation, of 30 extensively characterized PDAC cases - part of the Australia ICGC (International Cancer Genome Consortium) program, Avner Pancreatic Cancer Biobank and PURPLE Registry.
The PDAC TME is immunosuppressive, yet the dynamics and cellular heterogeneity within the immune microenvironment remain largely unresolved. In the lymphoid components, we identified two major CD8+ T cell populations, GZMK+ and ITGAE+, each differentially expresses distinct immune checkpoint regulators, TIGIT and LAG3/HAVCR2, respectively, underlining the need for multiple checkpoint inhibitors to effectively target these CD8+ T cells for anti-tumour immunity. Ligand-receptor interaction analysis predicted diverse sources of immune checkpoint ligands within the TME that could contribute to immune suppression and modulation in CD8+ T cells. Cytolytic functions in NK were notably suppressed by signals from macrophages. On the contrary, macrophages exhibit significant heterogeneity, including CLEC5A+ macrophages with antigen-presenting roles, C1QC+ macrophages with phagocytic activities, and tumour associated macrophages (TAM) with a distinctive metabolic profile associated with immunosuppression. TAMs display distinct transcriptional states. SPP1+ TAMs resembled lipid-associated macrophages, expressing CCL18 and producing granulin, and highly associated with liver metastasis in PDAC. Another critical TAM state, THBS1+, highly express the MDSC-associated marker OLR1, along with angiogenic factor VEGFA and mitogen HBEGF, indicate potential roles in supporting angiogenesis and tumour growth.
In summary, our analysis uncovered the transcriptional diversity of immune cells within the TME and highlighted the macrophage subsets that shape the immune-suppressive landscape and contribute to tumour growth in PDAC.