Pancreatic cancer (PaC) is resistant to immune checkpoint
therapy, but the underlying mechanisms are largely unknown. In this study, we have established four orthotopic PaC murine models with different PaC cell lines by intra-pancreatic inoculation. Therapeutic examinations demonstrate that only
tumors induced with Panc02-H7 cells respond to αPD-1 antibody treatment, leading to significantly reduced
tumor growth and increased survival in the recipient mice. Transcriptomic profiling at a single-cell resolution characterizes the molecular activity of different cells within
tumors. Comparative analysis and validated experiments demonstrate that αPD-1-sensitive and -resistant
tumors differently shape the immune landscape in the tumor microenvironment (TME) and markedly altering effector CD8+ T cells and tumor-associated macrophages (TAMs) in their number, frequency, and gene profile. More exhausted effector CD8+ T cells and increased M2-like TAMs with a reduced capacity of antigen presentation are detected in resistant Panc02-formed
tumors versus responsive Panc02-H7-formed
tumors. Together, our data highlight the correlation of
tumor-induced imbalance of macrophages with the fate of
tumor-resident effector CD8+ T cells and PaC response to αPD-1
immunotherapy. TAMs as a critical regulator of
tumor immunity and
immunotherapy contribute to PaC resistance to
immune checkpoint blockade.