In this study we investigated whether the presence of specific populations of tumor infiltrating lymphocytes (TILs) in diagnostic primary melanoma biopsies are related to outcome in clinically stage II melanoma patients. Moreover, we investigated whether the presence of TILs correlates with expression of MHC class I antigen and MHC class II antigen on tumor cells and/or tumor infiltrating antigen presenting cells. Diagnostic primary melanoma samples of 15 patients with an unfavorable outcome were compared with 20 patients with favorable outcome. Patients were matched for age, gender and Breslow thickness. Biopsies were examined for the presence of granzyme B 1 , CD8 1 , CD4 1 and CD56 1 TILs and for expression of MHC class I antigen and MHC class II antigen on tumor and/or tumor infiltrating cells. A favorable clinical outcome was strongly associated with the presence of GrB 1 and CD4 1 TILs, with expression of MHC class I antigen on tumor cells and with expression of MHC class II antigen on intratumoral antigen presenting cells. These data strongly support the notion that in melanoma patients the cellular immune response is a major factor in preventing melanoma cell dissemination. ' 2008 Wiley-Liss, Inc.Key words: TILs; granzyme B; MHC class I; MHC class II; prognosis; CD4; CD8 Even though melanomas account for only 4% of all skin cancers, they cause the greatest number of skin cancer-related deaths worldwide. Over the last few decades an increase in incidence and mortality has been observed in Caucasian populations across the world. 1,2 Clinical outcome in melanoma patients depends on several variables of which tumor thickness is an important factor (according to Breslow). 3 The 5 year survival rate for patients with a Breslow thickness <1.5 mm is more than 90%, whereas survival in patients with a Breslow thickness of >3.5 mm is only 50%. 4 Other important prognostic factors are, amongst others, gender and age. [5][6][7] Fatal outcome in melanoma patients often results from occurrence of distant metastases, which mostly coincide or are preceded by lymph node metastases. In line with this concept, previous studies demonstrated that patients with a melanoma sentinel lymph node (SLN) metastasis have a worse prognosis than patients without a SLN metastasis. 8,9 However, despite known prognostic parameters, outcome often remains unpredictable and further research to identify additional relevant prognostic markers is warranted.It has previously been shown that melanomas can elicit an immune response 10,11 and that melanoma cells can effectively be eradicated in vivo by cytotoxic activity of MHC class I antigen restricted CD8 1 Granzyme B (GrB 1 ) T-cells. 12 Thus, a possible explanation for differences in clinical outcome might be that a proper immune response, although incapable of preventing the primary tumor from growing, is able to prevent the occurrence of lymph node and/or distant metastases. A large number of studies have shown that the cellular immune response plays an important role in the control of melan...

Key Points Amplification of 1q21 correlates with increased sensitivity to MCL-1 inhibitor S63845 in primary MM cells. Poor-prognosis MM is particularly sensitive to MCL-1 inhibition, partially independent of 1q21 amplification status.

Pro-survival BCL-2 family members protect cells from programmed cell death that can be induced by multiple internal or external cues. Within the haematopoietic lineages, the BCL-2 family members BCL-2, BCL-XL and MCL-1 are known to support cell survival but the individual and overlapping roles of these pro-survival BCL-2 proteins for the persistence of individual leukocyte subsets in vivo has not yet been determined. By combining inducible knockout mouse models with the BH3-mimetic compound ABT-737, which inhibits BCL-2, BCL-XL and BCL-W, we found that dependency on MCL-1, BCL-XL or BCL-2 expression changes during B-cell development. We show that BCL-XL expression promotes survival of immature B cells, expression of BCL-2 is important for survival of mature B cells and long-lived plasma cells (PC), and expression of MCL-1 is important for survival throughout B-cell development. These data were confirmed with novel highly specific BH3-mimetic compounds that target either BCL-2, BCL-XL or MCL-1. In addition, we observed that combined inhibition of these pro-survival proteins acts in concert to delete specific B-cell subsets. Reduced expression of MCL-1 further sensitized immature as well as transitional B cells and splenic PC to loss of BCL-XL expression. More markedly, loss of MCL-1 greatly sensitizes PC populations to BCL-2 inhibition using ABT-737, even though the total wild-type PC pool in the spleen is not significantly affected by this drug and the bone marrow (BM) PC population only slightly. Combined loss or inhibition of MCL-1 and BCL-2 reduced the numbers of established PC >100-fold within days. Our data suggest that combination treatment targeting these pro-survival proteins could be advantageous for treatment of antibody-mediated autoimmune diseases and B-cell malignancies.

c-FLIP is important in escape of B cells from apoptosis during normal follicle centre cell reaction and may thus be an important early event in the development of B-cell-derived lymphomas. Moreover, non-specific staining of frequently used antibodies might explain discrepancies in different reports of c-FLIP expression.