Until now, melanoma remains refractory to most chemotherapies and immunotherapeutic strategies have shown only limited success. One escape mechanism used by tumor cells to avoid the destruction by the immune system is down-regulation of molecules of the antigen-presenting machinery. Thus, many tumor cells have low or absent expression of major histocompatibility complex class I (MHC-I) molecules on their surface, and consequently, do not present tumor-specific peptides on the outer membrane. Such a phenomenon prevents the activity of tumor-specific cytotoxic T lymphocytes (CTL), but renders the tumor cells vulnerable to natural killer (NK) cells.
In this study, we used the murine B16 melanoma model to analyse the ability of tumor cells to repress or not MHC-I expression under immunological or pharmacological pressure.
We discovered that MHC-Ilow expressing tumor cells cultured with normal syngeneic spleen cells (NSC) were induced to re-express MHC-I molecules. Cell-fractionation studies as well as studies with NSC from mice with deficiencies in certain cell populations (either by genetic means, or by depletion with mAb-injection) demonstrated that CD4+, Thy1+, Ig- cells contained effector cells involved in the regulation of MHC-I expression on tumor cells. NK cells seemed also implicated as NSC from rag-/- mice have MHC-I augmenting activity though less strong than NSC from wild-type mice. Cell-cell contact between MHC-Ilow tumor cells and NSC was a necessary step, which resulted in IFNγ production and a consequent increased in MHC-I expression. IFN-γ is known to induce MHC-I expression in a number of MHC-Ilow expressing tumor cells, suggesting a possible anti-tumor therapeutic application. However clinical trials failed to show benefit to cancer patients treated with IFN-γ.
We then screened a set of anticancer molecules, either cytotoxic or cytostatic, for their ability to induce MHC-I molecules on the surface of B16 melanoma cells. Cells treated with 10μM gemcitabine showed significantly increased MHC-I expression. Expressed MHC-I molecules were functional since presentation of antigenic peptides was restored as well as sensitization of the tumor cells to recognition and lysis, although weak, by CTL.
Our data support a growing line of evidence that combining chemo- and immuno-therapeutic means may represent an improved alternative to chemotherapy or immunotherapy alone of melanoma.
(the first two authors contributed equally to this work)
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA