The resurgence of cancer immunotherapy stems from an improved understanding of 
the tumor microenvironment. The PD-1/PD-L1 axis is of particular interest, in 
light of promising data demonstrating a restoration of host immunity against 
tumors, with the prospect of durable remissions. Indeed, remarkable clinical 
responses have been seen in several different malignancies including, but not 
limited to, melanoma, lung, kidney, and bladder cancers. Even so, determining 
which patients derive benefit from PD-1/PD-L1-directed immunotherapy remains an 
important clinical question, particularly in light of the autoimmune toxicity of 
these agents. The use of PD-L1 (B7-H1) immunohistochemistry (IHC) as a 
predictive biomarker is confounded by multiple unresolved issues: variable 
detection antibodies, differing IHC cutoffs, tissue preparation, processing 
variability, primary versus metastatic biopsies, oncogenic versus induced PD-L1 
expression, and staining of tumor versus immune cells. Emerging data suggest 
that patients whose tumors overexpress PD-L1 by IHC have improved clinical 
outcomes with anti-PD-1-directed therapy, but the presence of robust responses 
in some patients with low levels of expression of these markers complicates the 
issue of PD-L1 as an exclusionary predictive biomarker. An improved 
understanding of the host immune system and tumor microenvironment will better 
elucidate which patients derive benefit from these promising agents.