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• Membrane PD-L1 expression was rarely observed in the presence of ALK rearrangements. • Tumor bed infiltration CD8 + T cell more frequent in tumors with ALK mutations. • CD8+ T cells infiltrating ALK+ tumors were unable to express IFNG. Several lines of evidence have demonstrated that programmed cell death 1 (PD-1) inhibitors as monotherapies for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer have little clinical activity. The underlying mechanisms remain not understood. In this study, using immunohistochemistry and in situ RT-PCR assays, we examined the expression of programmed cell death ligand 1 (PD-L1), PD-1, CD8, and interferon gamma (IFN-γ) in tumors. Both epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-positive tumors were associated with low or absent membrane PD-L1 expression. Interestingly, unlike EGFR-mutant tumors with few tumor-infiltrating CD8+ T cells, a significant number of PD-1-positive CD8+ T cells infiltrated the ALK-positive tumor bed; however, these cells did not express IFNG mRNA. These results demonstrate that the ALK-positive tumor microenvironment suppresses the immune function of tumor-infiltrating CD8+ T cells through a PD-1/PD-L1-independent mechanism, which might lead to the inability of ALK-positive tumors to respond to PD-1/PD-L1-based immunotherapy. [ABSTRACT FROM AUTHOR]