Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB.,We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples.,We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs.,These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays.,We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism.,Furthermore, we analyzed additional clinical samples from another large melanoma cohort.,Two patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers.,Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively.,TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient.,CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation.,Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models.,In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance.,The TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer.
An important checkpoint in the progression of melanoma is the metastasis to lymph nodes.,Here, to investigate the role of lymph node NK cells in disease progression, we analyze frequency, phenotype and functions of NK cells from tumor-infiltrated (TILN) and tumor-free ipsilateral lymph nodes (TFLN) of the same patients.,We show an expansion of CD56dimCD57dimCD69+CCR7+KIR+ NK cells in TILN.,TILN NK cells display robust cytotoxic activity against autologous melanoma cells.,In the blood of metastatic melanoma patients the frequency of NK cells expressing the receptors for CXCL8 receptor is increased compared to healthy subjects, and blood NK cells also express the receptors for CCL2 and IL6.,These factors are produced in high amount in TILN and in vitro switch the phenotype of blood NK cells from healthy donors to the phenotype associated with TILN.,Our data suggest that the microenvironment of TILN generates and/or recruits a particularly effective NK cell subset.