IL-10 expression by primary tumor cells correlates with melanoma progression from radial to vertical growth phase and development of metastatic competence

Abstract

Down-regulation of the immune system facilitates tumor progression at different stages of cutaneous melanoma. Sentinel nodes, the first lymph nodes on lymphatics draining directly from a primary melanoma are immune down-regulated by tumor-generated immune-suppressive cytokines including interleukin-10. To better understand the kinetics of sentinel node suppression, we investigated interleukin-10 expression by melanoma cells and tumor-associated macrophages and lymphocytes at different stages of primary melanoma evolution. We used reverse transcriptase in situ polymerase chain reaction to identify cellular sources of interleukin-10 mRNA in 39 melanomas. Interleukin-10 mRNA was identified in tumor cells of 2/6 melanomas in situ (33%), 17/21 invasive melanomas (81%) and 11/12 metastatic melanomas (92%). Higher interleukin-10 expression correlates with tumor progression, with differences between melanoma in situ, invasive melanoma and metastatic melanoma. In primary melanomas, the interleukin-10 mRNA content of tumor cells correlates with Clark level. There was significantly more interleukin-10 mRNA in vertical growth phase melanoma cells than in radial growth phase cells. In a logistic regression model, moderate to high interleukin-10 mRNA expression by tumor cells was significantly associated with vertical growth phase melanoma. Interleukin-10 mRNA was detected in melanoma-associated macrophages and lymphocytes. In invasive melanomas, the interleukin-10 mRNA reactivity of macrophages declined as Clark level increased. Alterations of immunity by interleukin-10 derived from melanoma cells and melanoma-associated macrophages and lymphocytes potentially facilitate evolution of the primary melanoma and render regional lymph nodes susceptible to metastases.

Glioma Grade Is Associated with the Accumulation and Activity of Cells Bearing M2 Monocyte Markers

“…Mean survival of the CD163 high and low cohorts was 39 AE 10 and 286 AE 95 weeks, respectively (P ¼ 0.01 by the log-rank test). IL-10 has well-established immunomodulatory properties and is elaborated by a number of different cell types in a variety of cancers including melanoma (42), non-small cell lung cancer (43), and B-cell lymphoma (44) as well as glioblastoma multiformes. This has led to speculation that IL-10 contributes to an immunosuppressive tumor microenvironment, a concept that is challenged by the observation ÃÃÃ , statistically significant difference between the groups determined by the MannWhitney U test (P < 0.001).…”

The Non–Small Cell Lung Cancer Immune Contexture. A Major Determinant of Tumor Characteristics and Patient Outcome

“…It has also been reported that lung cancer cells are able to produce immunosuppressive factors in the tumor microenvironment. For example, they can secrete a soluble form of MHC class I chain-related molecule A, inducing downregulation of NKG2D expression of CD8 IL-10 or TGF-b or the tryptophan catabolic enzyme indoleamine 2,3-dioxygenase, which are key players involved in the inhibition of immune responses and enhancing the proliferation of cancer cells (56,57). Lung cancer cells, among other components of the tumor microenvironment, express chemokine receptors and produce chemokines that regulate the trafficking of immune and cancer cells.…”

The Role of Cytokines and Chemokines in the Development of Basal Cell Carcinoma

“…BCC is regarded as an indolent (slow growing) cancer with limited metastatic potential. While IL-10 expression by melanoma cells correlates with melanoma progression and development of metastatic competence (18), there is no clear correlation between IL-10 expression and tumor invasiveness of BCC. IL-10 can be detected by both aggressive BCC and nonaggressive BCC such as superficial BCC.…”