MAP Kinase inhibition reshapes tumour microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages

Pancreatic ductal adenocarcinoma (PDAC) is a pancreatic disease with the lowest survival rate of all cancers. The current therapeutic strategies provide only marginal increase in patients’ survival. It has been recently demonstrated that the tumor microenvironment (TME) plays a major role in the resistance to therapy. Four subtypes of PDAC have been defined based on mRNA profiling of primary tumors. Of these, two (Immunogenic and Squamous) possess high expression of immune-related transcripts, including a macrophage transcriptional signature that indicates worse patients’ survival. Despite important phenotypic differences, all subtypes present activating mutations of KRAS. Activated KRAS engages the MAP Kinase pathway, which has been the index oncogenic signaling towards which many compounds have been developed and tested for the treatment of KRAS-driven cancers. We showed that transcriptional signatures of downstream Ras signaling (MAP kinase) are enriched in human PDAC subtypes dominated by immune-related transcripts (Immunogenic and Squamous). We found that increased MAP kinase transcriptional output is observed in biologically-aggressive PDAC subtypes (Squamous/Basal-like). We used preclinical models of PDAC to demonstrate that MEK inhibition promoted tumor infiltration by leukocytes. Integrative mRNA expression and immunophenotypic analyses showed that MEKi relieved immunosuppression in the TME by reducing the number of anti-inflammatory M2 macrophages and favored infiltration of CD8 positive T cells. The same MEKi-induced M2 depletion was also observed in PDAC tissues from an independent isografts as well as in a genetically-engineered mouse model (GEMM) of PDAC. We showed that depletion of M2 macrophages is seen early during the course of the in vivo treatment, and it is likely due to increased drug sensitivity of M2 macrophages compared to the other macrophage phenotypes. In addition, MEKi induces a “switch away” from the Squamous/Basal-like subtype and a significant deregulation of a “squamous” gene program. Taken together, our data show that MEKi influences the TME in PDAC by depleting M2 macrophages and favoring infiltration of T cells. As tumor-associated macrophages have been reported to impair chemotherapy efficacy in PDAC, MEKi-induced depletion of M2 macrophages could be exploited to increase treatment efficacy in PDAC.