A subgroup of melanomas shows constitutive expression of surface HLA class II (HLA-II) molecules, presenting antigens to CD4+ T cells. The HLA-II gene network is controlled by the master regulator CIITA and includes genes encoding the antigen presenting HLA-DR, -DP, -DQ molecules as well as accessory components involved in HLA-II assembly. Among normal cells, only professional antigen presenting cells (pAPCs), like dendritic cells, macrophages and B cells show constitutive CIITA/HLA-II (constCIITA/HLA-II) expression, in line with their function of controlling primary CD4+ T cell activation. In other cell types (non-APCs), expression of CIITA and HLA-II is induced in response to JAK-STAT pathway activation by the inflammatory cytokine IFNγ. In this regard, the IFNγ-independent constCIITA/HLA-II melanoma cell phenotype is rather exceptional.
On the one hand constCIITA/HLA-II expression in melanoma cells is considered anti-tumorigenic as it can lead to the activation of tumor-reactive cytotoxic CD4+ T cells, on the other hand constCIITA/HLA-II expression has been associated with pro-tumorigenic stem cell-like properties. So far, the molecular mechanisms driving development of the constCIITA/HLA-II melanoma cell phenotype are largely unknown.

In the first funding period (FP1) of the Clinical Research Unit PhenoTImE, our studies found constCIITA/HLA-II expression in melanoma cells restricted to specific differentiation states. Using various patient models of paired HLA-DRpos and HLA-DRneg melanoma cells, we recognized higher drug resistance of the HLA-DRpos constCIITA/HLA-II tumor cell phenotype.
Moreover, we observed that the constCIITA/HLA-II phenotype was enriched among the drug-induced resistant cell states not only in melanoma but also pancreatic cancer. Within FP2, the Clinical Research Unit PhenoTImE will provide a unique platform that will allow us to (i) define differentiation state-specific regulators of constCIITA/HLA-II expression, (ii) track constCIITA/HLA-II melanoma cells under persistent drug treatment to determine their intrinsic resistance potential, and (iii) therapeutically target the constCIITA/HLA-II melanoma cell phenotype with CD4+ T cells in the preclinical setting.

Targeting of the constCIITA/HLA-II melanoma cell phenotype could be an efficient strategy to overcome therapy resistance in melanoma with immediate implications for the design of personalized clinical trials. Moreover, molecular dissection of the constCIITA/HLA-II melanoma cell phenotype could lead to the development of new biomarkers and companion diagnostics in the near future.

Contact

Prof. Dr. rer. nat. Annette Paschen

Department of Dermatology
German Cancer Consortium (DKTK)
niversity Hospital Essen

Lab homepage