Favorable outcome in clinically stage II melanoma patients is associated with the presence of activated tumor infiltrating T‐lymphocytes and preserved MHC class I antigen expression

Abstract

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...

Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma

“…The current study suggests that the treatment of patients with a BRAF inhibitor may increase both Th-cell and cytotoxic T-cell responses against the tumor and that this may contribute to their therapeutic effects. Previous studies have shown that increased expression of Granzyme B-expressing CD8 þ (active) and CD4 þ cells in stage II melanoma biopsies correlated with a favorable outcome (19). The results in the current study showing that an increase in the number of CD8 þ and Granzyme B þ T cells correlated with a decrease in posttreatment biopsied lesion diameter are consistent with these findings.…”

Highly clonal regulatory T-cell population in follicular lymphoma – inverse correlation with the diversity of CD8+T cells

“…17,18 A majority of studies have attempted to correlate numbers of tumor-infiltrating CD8 + T cells with clinical outcome, whereas none have, to our knowledge, analyzed TCR clonotypic diversity in relation to the anatomic location of T cells in FL tissues. In order to investigate whether a correlation between location (perifollicular versus intrafollicular) and the TCR diversity of CD8 + T cells exists in FL tissues, we undertook an immunohistochemical analysis of CD8 + T cells and compared it with CD8 + TCRb sequencing in these 6 FL samples.…”

Melanoma stem cells: not rare, but well done

“…102,104 Clinically, decreased MHC class I expression is associated with melanoma progression, therapeutic failure, and poor clinical outcome. [105][106][107] Interestingly, although suppression of MHC class I expression by melanoma stem cells may enable evasion from CD8 þ T lymphocytes of the adaptive immune response, low MHC class I expression would be predicted to increase their susceptibility to NK cells of the innate immune system, which are normally inhibited by MHC class I molecules. However, it is conceivable that melanoma stem cells may escape NK cells by altering their expression of additional surface molecules, such as NK cell ligands, which have activating or inhibitory effects on NK cells.…”