LAUSR

The last decade has seen explosive progress in understanding how tumor-associated macrophages (TAM) contribute to the development, metastasis, and therapy resistance of cancer. TAM and their molecular components are investigated as targets for cancer therapy. However, the precise mechanisms for their function remain to be fully elucidated. The p38 MAP kinase is known to play a pivotal role in cellular responses to stress, mitogenic stimuli, and immune signaling. Evidence from clinical observations and cell culture experiments reveals a role for p38 in many aspects of cancer and immunity. However, little is known about the functions of p38alpha, the most abundant and ubiquitously expressed p38 isoform, in TAM. Here we found that myeloid-specific p38alpha ablation resulted in a decrease in tumor incidence and multiplicity in a DMBA-TPA carcinogenesis model. Tumors from these mutant mice displayed markedly reduced proliferation and poorly developed blood vessels compared to those from control WT mice. Genome-wide expression analysis revealed that p38alpha ablation in macrophages resulted in enhanced CXCL9 expression, a chemokine crucial for cytotoxic T cell recruitment. Indeed, we observed greater number of tumor-infiltrating CD8+ T cells in myeloid-specific p38alpha-knockout mice. p38alpha indel mutations in THP-1 cells also led to elevated CXCL9 induction. TCGA data analysis revealed that higher intratumoral expression of CXCL9 was associated with prolonged survival of cancer patients, suggesting a beneficial effect of CXCL9 in human cancers. Next, we sought to identify the molecular mechanism linking p38alpha to the regulation of CXCL9 expression, and found that p38alpha directly phosphorylates and enables the induction of ATF3, a transcription factor that represses CXCL9 expression. Consistent with this finding, ATF3-deficient macrophages exhibited higher CXCL9 expression similar to p38alpha-deficient macrophages. Therefore, macrophage-specific targeting of p38alpha signaling may promote cytotoxic T cell recruitment to the tumor microenvironment and maximize the potential of checkpoint inhibitor and CAR T cell therapies and other therapeutic modalities that rely on tumor-killing CD8+ T cells. Citation Format: Min-Kyung Choo, Jin Mo Park. Myeloid p38 MAPK promotes tumorigenesis by suppressing cytotoxic T cell recruitment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B11. doi:10.1158/1535-7163.TARG-19-LB-B11