IMMUNE-RESPONSE AGAINST HUMAN PRIMARY MALIGNANT-MELANOMA - A DISTINCTCYTOKINE MESSENGER-RNA PROFILE ASSOCIATED WITH SPONTANEOUS REGRESSION

Spontaneous regression of melanoma lesions is thought to be the result of an efficient immune response against melanoma cells in vivo. The o utcome of immune responses is critically influenced by a complex netwo rk of interacting cytokines present in the local microenvironment. Ana lysis of cytokine gene transcription in melanoma lesions exhibiting or lacking a sufficient anti-tumor immune response thus may help to defi ne cytokines or cytokine combinations critical to the development of t his immune response. In the present study, we have investigated an ext ended panel of cytokine and cytokine receptor genes by reverse transcr iption-PCR and in situ hybridization in regressive and progressive pri mary human cutaneous melanoma samples. Whereas the presence of a lymph ocyte infiltrate in tissue samples was associated with a T(H)1 cytokin e mRNA profile (TNF-alpha, INF-gamma, IL12p35, IL12p40, IL2R beta, and IL2R gamma), clinically and histologically regressive samples exhibit ed additionally increased transcript levels for GM-CSF, IL2, and IL15. mRNAs of T(H)2 cytokines IL4 and IL5 were detected only in a minor po rtion of progressive melanoma samples and regressive melanoma lesions. These results were further supported by comparison of progressive wit h regressive regions in three melanoma samples. Again, regressive regi ons contained higher transcript levels for GM-CSF, IL2, and IL15. In c omparison to cutaneous metastatic melanoma lesions, regressive melanom as also overexpressed the same cytokine mRNA profile. These results pr ovide evidence for an association of spontaneous regression with incre ased transcript levels for the cytokine combination GM-CSF, IL2, and I L15 in malignant melanoma. This cytokine combination could be relevant for experimental anti-tumor immune response studies and for immunothe rapeutic and gene transfer studies in the treatment of melanoma patien ts.