Convergent identification and interrogation of tumor-intrinsic factors for immune escape in vivo

Evading immune destruction is a hallmark of cancer and a key feature for theresistance to cancer immunotherapy. Genetic alterations can directly influence thenature of cancer cells in the native tumor microenvironment to mediate immuneescape. Our genome-scale in vivo CRISPR screens robustly identified multipleregulators of tumor-intrinsic factors that alter the ability of cells to grow as tumorsacross different levels of immunocompetence. As a convergent hit from these screens,Prkar1a mutant cells are able to robustly outgrow as tumors in fully immunocompetenthosts. Functional interrogation showed that Prkar1a loss greatly altered thetranscriptome and proteome involved in inflammatory and immune responses as wellas extracellular protein production. Single cell transcriptomic profiling and flowcytometry analysis mapped the tumor microenvironment of Prkar1a mutant tumors,and revealed the transcriptomic alterations in host myeloid cells. Taken together,tumor-intrinsic mutations in Prkar1a led to drastic alterations in the genetic program ofcancer cells, thereby remodeling the tumor microenvironment.