CRISPR screen to underpin the transcription factor network of macrophage plasticity in tumors

Macrophage plasticity is an important physiological phenomenon in health and disease. Macrophages perform a multitude of functions such as immune response and homeostasis. Their activation status depends on the surrounding milieu tuning them to be either M1 (pro-inflammatory/anti-tumor) or M2 (anti-inflammatory/pro-tumor). Tumors exploit macrophage plasticity by skewing them towards M2 for escaping immune surveillance propagation, angiogenesis, and invasion. Macrophages represent most-of the leukocytic population in the tumor microenvironment (TME). Neoplastic cells release chemokines that recruit macrophages into the tumor mass, where they provide factors like MMPs, cathepsins, VEGF, PDGF, FGF CXCL8 and CXCL20 that facilitate tumor growth. In pancreatic ductal carcinoma (PDAC), infiltration of M2 macrophages plays a pivotal role in tumor progression, epithelial-mesenchymal transition, and metastasis. Targeting macrophages to modulate their immunosuppressive effect or reducing the number of macrophages in the tumor mass showed encouraging effects in reducing tumor growth. However, the transcription factor network that derives the transition of macrophages to M2 in the TME remains obscure. We performed CRISPR screen to inhibit the M2 program and found a set of transcription regulators and chromatin binding proteins such as PLAGL2, KMT2D, SPI1, and SAP130 that can be rewired to reverse the phenotype of macrophages. Reprograming the M2 macrophage to M1, is an interesting avenue to suppress tumor growth and develop new immunotherapeutic strategies.