Recently, it has been described that programmed cell death protein 1 (PD-1) overexpressing melanoma cells are highly aggressive.,However, until now it has not been defined which factors lead to the generation of PD-1 overexpressing subpopulations.,Here, we present that melanoma-derived exosomes, conveying oncogenic molecular reprogramming, induce the formation of a melanoma-like, PD-1 overexpressing cell population (mMSCPD-1+) from naïve mesenchymal stem cells (MSCs).,Exosomes and mMSCPD-1+ cells induce tumor progression and expression of oncogenic factors in vivo.,Finally, we revealed a characteristic, tumorigenic signaling network combining the upregulated molecules (e.g., PD-1, MET, RAF1, BCL2, MTOR) and their upstream exosomal regulating proteins and miRNAs.,Our study highlights the complexity of exosomal communication during tumor progression and contributes to the detailed understanding of metastatic processes.
Antibodies against programmed cell death-1 (PD-1) have considerably changed the treatment for melanoma.,However, many patients do not display therapeutic response or eventually relapse.,Moreover, patients treated with anti-PD-1 develop immune-related adverse events that can be cured with anti-tumor necrosis factor α (TNF) antibodies.,Whether anti-TNF antibodies affect the anti-cancer immune response remains unknown.,Our recent work has highlighted that TNFR1-dependent TNF signalling impairs the accumulation of CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) in mouse melanoma.,Herein, our results indicate that TNF or TNFR1 blockade synergizes with anti-PD-1 on anti-cancer immune responses towards solid cancers.,Mechanistically, TNF blockade prevents anti-PD-1-induced TIL cell death as well as PD-L1 and TIM-3 expression.,TNF expression positively correlates with expression of PD-L1 and TIM-3 in human melanoma specimens.,This study provides a strong rationale to develop a combination therapy based on the use of anti-PD-1 and anti-TNF in cancer patients.,Most melanoma patients do not respond to anti-PD1 therapy.,Here, the authors show that TNFα blockade synergizes with anti-PD-1 by preventing anti-PD-1-induced CD8+ T cell death and TIM-3 expression on such cells.