Compositions and methods comprising digital signatures to predict response and resistance to targeted therapy and immunotherapy

A method of determining whether inhibition of cytotoxic T-lymphocyte-associated protein 4 (CTLA4), programmed cell death protein 1 (PD1), or programmed death-ligand 1 (PD-L1) in a subject with neoplasia will result in clinical benefit in the subject comprising:

• obtaining a test sample from a subject having or at risk of developing neoplasia;
• determining the expression level of at least one tumor immune dysfunction and exclusion (TIDE)-associated gene in the test sample;
• comparing the expression level of the TIDE-associated gene in the test sample with the expression level of the TIDE-associated gene in a reference sample;
• and
• determining whether CTLA4, PD1, or PD-L1 blockade will inhibit neoplasia in the subject if the expression level of the TIDE-associated gene in the test sample is differentially expressed as compared to the level of the TIDE-associated gene in the reference sample.