Project Details
Projekt
Dissecting and targeting HLA class II-positive melanoma cell states in therapy resistance
Applicant
Professorin Dr. Annette Paschen
Subject Area
Dermatology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 405344257
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 IFN. In this regard, the IFN-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.
DFG Programme
Clinical Research Units
