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However, immune evasion, downregulation of immune function by the tumour microenvironment and resistance of cancer cells are major problems. Although CTL and NK cells are both important to eliminate cancer, most studies address them individually. We quantified sequential primary human CTL and NK cell cytotoxicity against the melanoma cell line SK\u2010Mel\u20105. At high effector\u2010to\u2010target ratios, NK cells or melan\u2010A (MART\u20101)\u2010specific CTL eliminated all SK\u2010Mel\u20105 cells within 24\u00a0h, indicating that SK\u2010Mel\u20105 cells are not resistant initially. However, at lower effector\u2010to\u2010target ratios, which resemble numbers of the immune contexture in human cancer, a substantial number of SK\u2010Mel\u20105 cells survived. Pre\u2010exposure to CTL induced resistance in surviving SK\u2010Mel\u20105 cells to subsequent CTL or NK cell cytotoxicity, and pre\u2010exposure to NK cells induced resistance in surviving SK\u2010Mel\u20105 cells to NK cells. Higher human leucocyte antigen class I expression or interleukin\u20106 levels were correlated with resistance to NK cells, whereas reduction in MART\u20101 antigen expression was correlated with reduced CTL cytotoxicity. The CTL cytotoxicity was rescued beyond control levels by exogenous MART\u20101 antigen. In contrast to the other three combinations, CTL cytotoxicity against SK\u2010Mel\u20105 cells was enhanced following NK cell pre\u2010exposure. Our assay allows quantification of sequential CTL and NK cell cytotoxicity and might guide strategies for efficient CTL\u2013NK cell anti\u2010melanoma therapies.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells eliminate cancer cells. Both CTL and NK cells attack the same targets, but most studies address them individually.<\/jats:p>\n <\/jats:list-item>\n \n In a sequential cytotoxicity model, the interdependence of antigen\u2010specific CTL and NK cell cytotoxicity against melanoma is quantified.<\/jats:p>\n <\/jats:list-item>\n \n High numbers of antigen\u2010specific CTL and NK cells eliminate all melanoma cells. However, lower numbers induce resistance if secondary CTL or NK cell exposure follows initial CTL exposure or if secondary NK cell exposure follows initial NK cell exposure. On the contrary, if secondary CTL exposure follows initial NK cell exposure, cytotoxicity is enhanced.<\/jats:p>\n <\/jats:list-item>\n \n Alterations in human leucocyte antigen class I expression and interleukin\u20106 levels are correlated with resistance to NK cells, whereas a reduction in antigen expression is correlated with reduced CTL cytotoxicity; CTL cytotoxicity is rescued beyond control levels by exogenous antigen.<\/jats:p>\n <\/jats:list-item>\n \n This assay and the results on interdependencies will help us to understand and optimize immune therapies against cancer.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp283667","type":"journal-article","created":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T03:40:09Z","timestamp":1665632409000},"page":"5027-5054","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Interdependence of sequential cytotoxic T 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