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Assessing the prognosis of patients with aggressive non-Hodgkin B cell lymphoma mainly relies on a clinical risk score (IPI). Standard first-line therapies are based on a chemo-immunotherapy with rituximab, which mediates CD16-dependent antibody-dependent cellular cytotoxicity (ADCC). We phenotypically and functionally analyzed blood samples from 46 patients focusing on CD16+ NK cells, CD16+ T cells and CD16+ monocytes. Kaplan-Meier survival curves show a superior progression-free survival (PFS) for patients having more than 1.6% CD16+ T cells (p = 0.02; HR = 0.13 (0.007–0.67)) but an inferior PFS having more than 10.0% CD16+ monocytes (p = 0.0003; HR = 16.0 (3.1-291.9)) at diagnosis. Surprisingly, no correlation with NK cells was found. The increased risk of relapse in the presence of > 10.0% CD16+ monocytes is reversed by the simultaneous occurrence of > 1.6% CD16+ T cells. The unexpectedly strong protective function of CD16+ T cells could be explained by their high antibody-dependent cellular cytotoxicity as quantified by real-time killing assays and single-cell imaging. The combined analysis of CD16+ monocytes (> 10%) and CD16+ T cells (< 1.6%) provided a strong model with a Harrell's C index of 0.80 and a very strong power of 0.996 even with our sample size of 46 patients. CD16 assessment in the initial blood analysis is thus a precise marker for early relapse prediction. Highlights: High CD16+ T cell counts have a positive correlation with PFS in aggressive NHL/DLBCL patients (p = 0.02; HR = 0.13, 0.01–0.7). High CD16+ monocyte counts have a negative correlation with PFS in aggressive NHL/DLBCL patients (p = 0.0003; HR = 16.0, 3-292). The combined assessment of CD16+ T cells and CD16+ monocytes accurately predicts PFS in aggressive NHL/DLBCL patients. The strong protective function of CD16+ T cells could be explained by their high antibody-dependent cellular cytotoxicity. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells recognize and eliminate cancer cells. 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‐Mel‐5. At high effector‐to‐target ratios, NK cells or melan‐A (MART‐1)‐specific CTL eliminated all SK‐Mel‐5 cells within 24 h, indicating that SK‐Mel‐5 cells are not resistant initially. However, at lower effector‐to‐target ratios, which resemble numbers of the immune contexture in human cancer, a substantial number of SK‐Mel‐5 cells survived. Pre‐exposure to CTL induced resistance in surviving SK‐Mel‐5 cells to subsequent CTL or NK cell cytotoxicity, and pre‐exposure to NK cells induced resistance in surviving SK‐Mel‐5 cells to NK cells. Higher human leucocyte antigen class I expression or interleukin‐6 levels were correlated with resistance to NK cells, whereas reduction in MART‐1 antigen expression was correlated with reduced CTL cytotoxicity. The CTL cytotoxicity was rescued beyond control levels by exogenous MART‐1 antigen. In contrast to the other three combinations, CTL cytotoxicity against SK‐Mel‐5 cells was enhanced following NK cell pre‐exposure. Our assay allows quantification of sequential CTL and NK cell cytotoxicity and might guide strategies for efficient CTL–NK cell anti‐melanoma therapies. Key points: 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.In a sequential cytotoxicity model, the interdependence of antigen‐specific CTL and NK cell cytotoxicity against melanoma is quantified.High numbers of antigen‐specific 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.Alterations in human leucocyte antigen class I expression and interleukin‐6 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.This assay and the results on interdependencies will help us to understand and optimize immune therapies against cancer. [ABSTRACT FROM AUTHOR]