The tumor microenvironment (TME) is a complex mixture of cell-types that interact with each other to affect tumor growth and clinical outcomes. To accelerate the discovery of such interactions, we developed CODEFACS (COnfident DEconvolution For All Cell Subsets), a deconvolution tool inferring cell-type-specific gene expression in each sample from bulk expression measurements, and LIRICS (LIgand Receptor Interactions between Cell Subsets), a supporting pipeline that analyzes the deconvolved gene expression from CODEFACS to identify clinically relevant ligand-receptor interactions between cell-types. Using 15 benchmark test datasets, we first demonstrate that CODEFACS substantially improves the ability to reconstruct cell-type-specific transcriptomes from individual bulk samples, compared to the state-of-the-art method, CIBERSORTx. Second, analyzing the TCGA, we uncover cell-cell interactions that specifically occur in TME of mismatch-repair-deficient tumors and are associated with their high response rates to anti-PD1 treatment. These results point to specific T-cell co-stimulating interactions that enhance immunotherapy responses in tumors independently of their mutation burden levels. Finally, using machine learning, we identify a subset of cell-cell interactions that predict patient response to anti-PD1 therapy in melanoma better than recently published bulk transcriptomics-based signatures. CODEFACS offers a way to study bulk cancer and normal transcriptomes at a cell type-specific resolution, complementing single-cell transcriptomics.

57Synapses are largely established during embryogenesis and maintained during 58 growth. The mechanisms that regulate synaptic allometry-the maintenance of 59 synaptic positions during growth-are largely unknown. We performed forward 60 genetic screens in C. elegans for synaptic allometry mutants and identified mig-61 17, a secreted metalloprotease of the conserved ADAMTS family. Through 62 proteomic mass spectrometry analyses, cell biological and genetic studies we 63 determined that MIG-17 is expressed by muscle cells to modulate glia location 64 and morphology. Glia are proximal to synapses, and the glial location and 65 morphology determine synaptic position during growth. Mig-17 regulates 66 synapse allometry by influencing epidermal-glia crosstalk through the 67 regulation of basement membrane proteins, including collagen type IV, SPARC 68 and fibulin. Our findings underscore the importance of glia location in the 69 maintenance of synaptic allometry, and uncover a muscle-epidermal-glia 70 signaling axis, mediated through the extracellular matrix, in the regulation of 71 glia morphology and synaptic positions during growth. 72 73 74 75 76 77 78 the level of identifying molecular factors necessary for maintaining synaptic 99 stability, density and morphology (Lin and Koleske, 2010;Luo et al.