melanoma is the most aggressive type of skin cancer. In Europe, almost 22 '000 deaths from this cancer were reported in 2012 (most recent statistics). Switzerland was then the country with the highest incidence (26.1 new diagnoses per year for the OO O’OOO inhabitants). Melanoma is also one of the cancers causing the highest immune reactions. A type of white blood cell, the cytotoxic T lymphocytes (CTLS), plays a key role in the fight against cancer. Indeed, CTLS can recognise, kill or change the behaviour of cancer cells. Their presence in human tumours has been associated with better prognosis. The CTLS are therefore at the heart of the spectacular progress of new immunotherapy cancer treatments. Despite the fundamental importance of CTLS infiltration into melanoma prognosis, the immediate reaction of melanoma cells to CTLS contact is still unknown. Indeed, many cancers are progressing despite the infiltration of CTLS. The immune system can counteract, but sometimes also foster the development of cancer. We assumed that CTLS could cause reactions in some cells related to cancer progression other than cell death. To study interactions between CTLS and melanoma cells, we developed a CTLS co-culture system with melanoma cell lines from different patients. The proteins of melanoma cells have been quantified by flow cytometry. Variations in gene expression in tumour cells were also assessed. We have seen that the response of tumour cells to contact the CTLS is very rapid, and that it is similar between the different melanoma lines. This response is largely driven by the IFNy and TNFA cytokines. These cytokines are secreted by the CTLS when recognising antigens specific to tumour cells. Benign melanocyte cell lines react similar to non-benign lines, suggesting that these reactions are not tumour specific. This response includes increasing secretion of soluble factors, and leads to many mechanisms that can both block and stimulate the immune system. In contact with CTLS, melanoma cells change the transcription of many genes, producing factors that will influence their immune environment. The homogeneity of the response contrasts with 1 genetic heterogeneity of melanoma lines. These results contribute to the best compensation of the immune mechanisms induced in the presence of CTLS, and could contribute to the improvement of immunotherapy treatments. — MELANOMA is the most aggressive type of skin cancer. In 2012 (latest statistics), 22 '000 deaths from MELANOMA were reported in Europe with the highest incidence in Switzerland (26.1 new diagnosis per year per ÎOO O O inhabitants). MELANOMA is also one of the most immunogenic cancer types (meaning it can provoke an immune response). In human tumors, the presence of cytotoxic T lymphocytes (CTLS), a specific type of white blood cell, has been associated with better clinical outcome. CTLS can recover and kill cancer cells or modify their behaviour, and are being exploited as a central player of immunotherapy with recent spectacular clinical outcome. Recognises the high importance of CTL infiltration for good prognosis, the actions of cancer cells to CTL attack are poorly characterised. In fact, many cancers progress in spite of tumor-infiltrating CTLS. Conversely, immune system components can counteract also support cancers, and we speculated that CTLS may cause responses in targeted cancer cells other than cell death that may be relevant to cancer progression. To investigate the interplay between CTLS and MELANOMA cells, we have established a co-culture system using CTLS and human MELANOMA cell Unes derived from different patients. We determined protein expression using multi-parameter flow cytometry, and gene expression using multiplexed expression analysis. We found rapid and predominant homogeneous changes in our MELANOMA cells in response to CTL attack. These responses were mostly mediated by the cytokines IFNy and TNFA Secreted by the CTLS on antigen-specific regeneration of the MELANOMA cells. Interestingly, benign melanocyte lines reacted to CTL attack in a similar way as MELANOMA cell lines, indicating that the shares were retained upon acquisition of malignancy. The MELANOMA response included incremented secretion of soluble factors that can appeal different immune cells to the tumor microenvironment and drive multiple immune activatory and inhibitory functions. In response to CTLS, MELANOMA cells modify their transcriptional program to produce immune-related factors and shape their immune microenvironment. The surprising homogeneity of the observed MELANOMA response contrasts to the genetic heterogeneity of MELANOMA cells. These results contribute to a better understanding of immune-related patients in cancer cells challenged by CTLS, and may possibly improve immunotherapy cancer.