A Novel Autocrine Pathway of Tumor Escape from Immune Recognition: Melanoma Cell Lines Produce a Soluble Protein That Diminishes Expression of the Gene Encoding the Melanocyte Lineage Melan-A/MART-1 Antigen Through Down-Modulation of Its Promoter

Kurnick, James T.; Ramirez-Montagut, Teresa; Boyle, Lenora A.; Andrews, David; Pandolfi, Franco; Durda, Paul J.; Butera, David; Dunn, Ian S.; Benson, Elizabeth M.; Gobin, Sam J. P.; Elsen, Peter J. van den

doi:10.4049/jimmunol.167.3.1204

Cited by 46 publications

(55 citation statements)

References 48 publications

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“…This is in line with data indicating that soluble proteins secreted by antigen-negative melanoma cells, such as cytokine oncostatin M, are capable of downregulating the expression of melanocyte differentiation genes. 45,46 It is also in line with the observation that IL-1 is upregulated in melanoma samples and that patients with IL-1 producing tumors have generally bad prognoses. 47 At first sight, interference with the IL-1 signaling in melanoma might, therefore, appear as a meaningful strategy to overcome the immunotherapeutic problem of low antigen expression.…”

Section: Tumor Immunologysupporting

confidence: 73%

Interleukins 1α and 1β secreted by some melanoma cell lines strongly reduce expression of MITF‐M and melanocyte differentiation antigens

Kholmanskikh

Baren

Brasseur

et al. 2010

Intl Journal of Cancer

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We report that melanoma cell lines expressing the interleukin-1 receptor exhibit 4-to 10-fold lower levels of mRNA of microphthalmia-associated transcription factor (MITF-M) when treated with interleukin-1b. This effect is NF-jB and JNKdependent. MITF-M regulates the expression of melanocyte differentiation genes such as MLANA, tyrosinase and gp100, which encode antigens recognized on melanoma cells by autologous cytolytic T lymphocytes. Accordingly, treating some melanoma cells with IL-1b reduced by 40-100% their ability to activate such antimelanoma cytolytic T lymphocytes. Finally, we observed large amounts of biologically active IL-1a or IL-1b secreted by two melanoma cell lines that did not express MITF-M, suggesting an autocrine MITF-M downregulation. We estimate that~13% of melanoma cell lines are MITF-M-negative and secrete IL-1 cytokines. These results indicate that the repression of melanocyte-differentiation genes by IL-1 produced by stromal cells or by tumor cells themselves may represent an additional mechanism of melanoma immune escape.

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Section: Tumor Immunologysupporting

confidence: 73%

Interleukins 1α and 1β secreted by some melanoma cell lines strongly reduce expression of MITF‐M and melanocyte differentiation antigens

Kholmanskikh

Baren

Brasseur

et al. 2010

Intl Journal of Cancer

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“…Further studies suggest that CTL against Melan-A/MART-1 are selected during T-cell development in the thymus, and that these T cells naturally respond to a variety of epitopes including viral and bacterial, but also crossreact with Melan-A/MART-1 epitopes . Antigen silencing of Melan-A/Mart-1 has been described through transcriptional downregulation induced by soluble factors produced by melanoma cells at high density (RamirezMontagut et al, 2000;Kurnick et al, 2001).…”

Section: Differentiation Antigensmentioning

confidence: 99%

Immunity to melanoma: unraveling the relation of tumor immunity and autoimmunity

et al. 2003

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“…[24][25][26] The heterogeneous nature of expression of these melanoma-associated antigens expression is related to antigen silencing during melanoma progression. Oncostatin M 27 secreted by melanoma cells 28 downregulates MART-1 and TRP-2. Microphthalmia transcription factor-M (MITF-M), a melanocyte-specific master transcription factor, may also regulate MART-1 expression.…”

Section: Discussionmentioning

confidence: 99%

RT in situ PCR detection of MART-1 and TRP-2 mRNA in formalin-fixed, paraffin-embedded tissues of melanoma and nevi

et al. 2008

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Melanoma antigen recognized by T cells 1 (MART-1) and tyrosinase-related protein-2 (TRP-2) are two useful markers for immunohistochemical detection of melanocytic tumors. However, these markers may be passively acquired (phagocytosed) rather than actively synthesized. Reverse transcriptase in situ polymerase chain reaction (RT in situ PCR) can amplify even small amounts of specific mRNA in cells and therefore confirm the cellular source of a marker. We developed a one-step RT in situ PCR procedure in which Thermus thermophilus DNA polymerase synthesizes and amplifies cDNA from mRNA in a single reaction mixture. To examine its practicability and feasibility with formalin-fixed, paraffin-embedded (FFPE) tissue, we compared the results of one-step RT in situ PCR with those of immunohistochemistry (IHC). MART-1 mRNA was identified in the cytoplasm of lesional cells from 23/26 primary melanomas (92%), 9/9 metastatic melanomas (100%) and 5/6 nevi (83%). MART-1 epitope was detected by IHC in 23/24 primary melanomas (96%), 9/9 metastatic melanomas (100%) and 5/6 nevi (83%). TRP-2 mRNA was identified in the cytoplasm of lesional cells from 17/26 primary melanomas (65%), 6/9 metastatic melanomas (67%) and 4/6 nevi (67%). TRP-2 epitope was detected by IHC in 20/ 24 primary melanomas (83%), 9/9 metastatic melanomas (100%) and 4/6 nevi (67%). Both techniques detected MART-1 and TRP-2 in FFPE melanoma cell lines. Neither marker was detected in squamous cell carcinomas or basal cell carcinomas by RT in situ PCR or IHC. We conclude that the RT in situ PCR technique can be successfully applied to FFPE tissue to determine the cellular sources of gene expression observed by conventional PCR approaches.

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A Novel Autocrine Pathway of Tumor Escape from Immune Recognition: Melanoma Cell Lines Produce a Soluble Protein That Diminishes Expression of the Gene Encoding the Melanocyte Lineage Melan-A/MART-1 Antigen Through Down-Modulation of Its Promoter

Cited by 46 publications

References 48 publications

Interleukins 1α and 1β secreted by some melanoma cell lines strongly reduce expression of MITF‐M and melanocyte differentiation antigens

Interleukins 1α and 1β secreted by some melanoma cell lines strongly reduce expression of MITF‐M and melanocyte differentiation antigens

Immunity to melanoma: unraveling the relation of tumor immunity and autoimmunity

RT in situ PCR detection of MART-1 and TRP-2 mRNA in formalin-fixed, paraffin-embedded tissues of melanoma and nevi

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