PD-1 blockade therapy has shown remarkable clinical responses in various cancers. This study investigates how pre-existing CD8+ T cells at the invasive tumor margin are associated with PD-1/PD-L1 immune inhibitory axis expression and may predict treatment response. Using immunohistochemistry, multiplex immunofluorescence, and next-generation sequencing, researchers analyzed 46 metastatic melanoma patients before and during pembrolizumab treatment. They found that responding patients had higher CD8, PD1, and PD-L1 expressing cells at the invasive margin and within the tumor, with closer proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. A predictive model based on CD8 expression at the invasive margin was validated in an independent cohort of 15 patients. The study suggests that tumor regression following PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1 mediated adaptive immune resistance. PD-L1, expressed by tumor cells, engages PD-1 on T cells, blocking effector functions and reducing T-cell killing capacity. PD-L1 can be constitutively expressed or induced by T cells producing interferons. This adaptive immune resistance is a mechanism by which cancer cells attempt to protect themselves from immune-cell mediated killing. The study found that pre-existing CD8+ T cells at the invasive margin are key factors in determining clinical response to PD-1 blocking therapy. The study also found that CD8+ T cell density at the invasive margin and tumor center correlated with treatment response. TCR sequencing showed that a more restricted TCR beta chain usage significantly correlated with clinical response to pembrolizumab treatment. The study built upon evidence that PD-L1 expression in tumors is associated with higher response rates to PD-1 or PD-L1 blocking antibodies. The study suggests that PD-L1 may serve as an indirect marker of adaptive immune resistance in response to tumor antigen-specific T cell infiltration rather than a static constitutive biomarker. Inducing a type-I interferon inflammatory response in combination with PD-L1 blockade merits further clinical investigation. T cell infiltrates have predictive value with respect to the natural history of primary cancers. The study found that baseline density and location of T cells in metastatic melanomas have predictive value in the treatment outcome of patients receiving therapies that block the PD-1/PD-L1 axis. Releasing the PD-1 immune checkpoint results in clinically relevant antitumor activity when there is a greater density of pre-existing tumor antigen-restricted CD8 T cells that are negatively regulated by PD-1/PD-L1 interactions.PD-1 blockade therapy has shown remarkable clinical responses in various cancers. This study investigates how pre-existing CD8+ T cells at the invasive tumor margin are associated with PD-1/PD-L1 immune inhibitory axis expression and may predict treatment response. Using immunohistochemistry, multiplex immunofluorescence, and next-generation sequencing, researchers analyzed 46 metastatic melanoma patients before and during pembrolizumab treatment. They found that responding patients had higher CD8, PD1, and PD-L1 expressing cells at the invasive margin and within the tumor, with closer proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. A predictive model based on CD8 expression at the invasive margin was validated in an independent cohort of 15 patients. The study suggests that tumor regression following PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1 mediated adaptive immune resistance. PD-L1, expressed by tumor cells, engages PD-1 on T cells, blocking effector functions and reducing T-cell killing capacity. PD-L1 can be constitutively expressed or induced by T cells producing interferons. This adaptive immune resistance is a mechanism by which cancer cells attempt to protect themselves from immune-cell mediated killing. The study found that pre-existing CD8+ T cells at the invasive margin are key factors in determining clinical response to PD-1 blocking therapy. The study also found that CD8+ T cell density at the invasive margin and tumor center correlated with treatment response. TCR sequencing showed that a more restricted TCR beta chain usage significantly correlated with clinical response to pembrolizumab treatment. The study built upon evidence that PD-L1 expression in tumors is associated with higher response rates to PD-1 or PD-L1 blocking antibodies. The study suggests that PD-L1 may serve as an indirect marker of adaptive immune resistance in response to tumor antigen-specific T cell infiltration rather than a static constitutive biomarker. Inducing a type-I interferon inflammatory response in combination with PD-L1 blockade merits further clinical investigation. T cell infiltrates have predictive value with respect to the natural history of primary cancers. The study found that baseline density and location of T cells in metastatic melanomas have predictive value in the treatment outcome of patients receiving therapies that block the PD-1/PD-L1 axis. Releasing the PD-1 immune checkpoint results in clinically relevant antitumor activity when there is a greater density of pre-existing tumor antigen-restricted CD8 T cells that are negatively regulated by PD-1/PD-L1 interactions.