Pluto Bioinformatics

GSE101336: RNA-seq in KPC mice treated with a hypomethylating drug (decitabine) and in untreated KPC mice

Bulk RNA sequencing

Background: Treatment with single-agent decitabine (5aza-dC; DAC), a well-tolerated DNA hypomethylating drug, in a mouse model of pancreatic ductal adenocarcinoma (PDAC), KPC-Brca1, extended the survival of the animals and upregulated immune-related pathways. Here we extend these findings to combination therapy, using DAC followed by the immune checkpoint inhibitor anti-PD-1H in the original more widely utilized KPC (Pdx-Cre Kras/p53) model. Methods: We treated tumor-bearing KPC mice with DAC, and with anti-PD-1H, separately and in combination, and assessed tumor growth, mouse survival, immune cell infiltration of the tumors, and gene expression, compared to historical and mock-treated control mice. Results: Treatment with single-agent DAC led to increased Cd8+ tumor-infiltrating T cells (TILs), increased tumor necrosis, and slower tumor growth. RNA-seq analysis revealed increased expression of a group of myeloid-lineage markers, including Chi3l3 (Ym1), which proved to reflect recruitment or expansion of a unique population of Chi3l3/Arginase-1 double-positive M2-polarized tumor-infiltrating myeloid cells. Anti-PD-1H alone had only modest effects on tumor growth and number of Cd8+ TILs. However, PD-1H-expressing TILs were significantly increased by single agent DAC, and DAC treatment followed by anti-PD-1H produced the strongest increase in Cd8+ TILS, inhibition of tumor growth, and prolongation of survival. Conclusions: Treatment with DAC alone, and DAC plus anti-PD-1H, inhibits PDAC tumor growth in the KPC model and produces changes in tumor-infiltrating lymphoid and myeloid cell populations, with an additive therapeutic benefit from combining the two agents. Since the influx of M2-polarized macrophages induced by DAC is predicted to antagonize the anti-tumor effects, future work should investigate eliminating or reprogramming these cells. SOURCE: Tamas Gonda (tg2214@columbia.edu) - Columbia University