Background: Tumor infiltrating lymphocytes (TIL) play a crucial role in the therapeutic impact of immune checkpoint blockers. Methods: We investigated metastases from 56 melanoma patients before and during treatment with immune checkpoint blockers (i) immunohistochemically, (ii) with TCR repertoire profiling and (iii) analysis of the transcriptome. The patients were treated with ipilimumab (n = 25) or pembrolizumab (n = 23) or ipilimumab/nivolumab (n = 7); half of them had a disease control, the other half progressed as best response to treatment. Results: In contrast to previous reports immunohistochemical analysis of the immune infiltrate revealed no significant difference in the number of CD8+ TILs in pretreatment samples of responders and non-responders. Instead, the number of CD4 + TILs including regulatory T cells (Treg) and the number of PD-1 + cells was higher in responders especially when receiving pembrolizumab. Samples taken at least 6 weeks after start of the immune checkpoint blocker showed a significant higher number of immune cells in responders through all T cell subsets (CD3,4,8,FoxP3, PD-1), B cells (CD20) as well as macrophages (CD68, CD163). TCR repertoire profiling by deep TCR sequencing demonstrated that responders develop a more diverse repertoire under treatment (p = 0.05). Pretreatment samples as well as the size of the top 10 TCR clones posttreatment did not differ significantly in responders and non-responders. By RNA sequencing no differential expression profiles between responders and non-responders was found pretreatment. Posttreatment samples expressed different genes compared to pretreatment samples in responders including MHC molecules, CDK2/4, Myc, TNF family members and different apoptosis-inducing genes. There was no differential gene expression in non-responders pre- and posttreatment. Conclusions: Pretreatment metastases from responders and non-responders do not differ much. With treatment responding patients have significant higher numbers of immune cells including T- and B- cells as well as macrophages and develop a more diverse TCR repertoire. RNA sequencing revealed a differential expression pre- versus posttreatment only in responding patients.