Combining transcriptomic and TCRαβ repertoire analysis of circulating and tumor-infiltrating CD8 T cells from patients with metastatic melanoma, Lucca et al. identify a blood-based population with effector properties that reflect those of clonally related tumor-resident T cells.,Understanding the relationship between tumor and peripheral immune environments could allow longitudinal immune monitoring in cancer.,Here, we examined whether T cells that share the same TCRαβ and are found in both tumor and blood can be interrogated to gain insight into the ongoing tumor T cell response.,Paired transcriptome and TCRαβ repertoire of circulating and tumor-infiltrating T cells were analyzed at the single-cell level from matched tumor and blood from patients with metastatic melanoma.,We found that in circulating T cells matching clonally expanded tumor-infiltrating T cells (circulating TILs), gene signatures of effector functions, but not terminal exhaustion, reflect those observed in the tumor.,In contrast, features of exhaustion are displayed predominantly by tumor-exclusive T cells.,Finally, genes associated with a high degree of blood-tumor TCR sharing were overexpressed in tumor tissue after immunotherapy.,These data demonstrate that circulating TILs have unique transcriptional patterns that may have utility for the interrogation of T cell function in cancer immunotherapy.
Brain metastases are the most common cause of death in patients with metastatic melanoma, and the RAF-MEK-ERK and PI3K-AKT signaling pathways are key players in melanoma progression and drug resistance.,The BRAF inhibitor vemurafenib significantly improved overall survival.,However, brain metastases still limit the effectiveness of this therapy.,In a series of patients, we observed that treatment with vemurafenib resulted in substantial regression of extracerebral metastases, but brain metastases developed.,This study aimed to identify factors that contribute to treatment resistance in brain metastases.,Matched brain and extracerebral metastases from melanoma patients had identical ERK, p-ERK, and AKT immunohistochemistry staining patterns, but there was hyperactivation of AKT (p-AKT) and loss of PTEN expression in the brain metastases.,Mutation analysis revealed no differences in BRAF, NRAS, or KIT mutation status in matched brain and extracerebral metastases.,In contrast, AKT, p-AKT, and PTEN expression was identical in monolayer cultures derived from melanoma brain and extracerebral metastases.,Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed higher AKT activation and invasiveness than melanoma cells stimulated by fibroblast-conditioned medium.,Inhibition of PI3K-AKT signaling resensitized melanoma cells isolated from a vemurafenib-resistant brain metastasis to vemurafenib.,Brain-derived factors appear to induce hyperactivation of the AKT survival pathway and to promote the survival and drug resistance of melanoma cells in the brain.,Thus, inhibition of PI3K-AKT signaling shows potential for enhancing and/or prolonging the antitumor effect of BRAF inhibitors or other anticancer agents in melanoma brain metastases.