Phenotypic Therapy and Immune Escape in Cancer
Project 4Defining the role of CIITA in tumor cell-intrinsic and CD4+ T cell-induced phenotype switching and therapy resistance
CIITA is the master regulator of a gene network involved in HLA class II (HLA-II) antigen presentation to CD4+ T cells. Professional antigen presenting cells (pAPCs) constitutively express CIITA (constCIITA) while in other cells CIITA is induced by IFNg via the JAK-STAT signaling pathway. Interestingly, a subgroup of melanoma cells shows JAK-STAT-independent constCIITA/HLA-II expression similar to pAPCs. The mechanisms leading to the establishment of a constCIITA/HLA-II tumor cell phenotype are poorly understood. In general, tumor cell-intrinsic constCIITA expression is considered anti-tumorigenic due to the constCIITA/HLA II-dependent activation of tumor antigen-specific CD4+ T cells and consequently the release of anti-proliferative pro-inflammatory T cell cytokines (IFNg,TNFα). In contrast, our preliminary work points to a so far undescribed pro-tumorigenic activity of tumor cell-intrinsic constCIITA. Our data suggest that a constCIITA-driven gene network enhances melanoma cell invasion and therapy resistance. Moreover, we find constCIITA expression in melanoma cells associated with a more de-differentiated phenotype. Hence, we hypothesize in this proposal that melanoma cell-intrinsic constCIITA controls a gene network with pro-tumorigenic activity enhancing tumor cell invasiveness, therapy resistance, and phenotype switching. Moreover we hypothesize that phenotype switching is further enhanced by the constCIITA-mediated ‘tumor-immune circuitry’ via pro-inflammatory T cell cytokines. The collaborations within the Clinical Research Unit PhenoTImE provide a unique platform that will allow us to elucidate (i) the mechanisms inducing constCIITA in melanoma, (ii) the constCIITA-driven gene network and its pro-tumorigenic activity, (iii) the role of the constCIITA/HLA-II melanoma phenotype in driving adaptive therapy-resistant cell state transition of surrounding cells by activation of cytokine release from CD4+ T cells. Targeting the constCIITA-driven gene network could represent a superior way of overcoming therapy and immune resistance in melanoma. This has immediate implications for the design of personalized clinical trials and could lead to the development of new biomarkers and companion diagnostics in the near future.
Prof. Dr. rer. nat. Annette Paschen
Department of Dermatology
German Cancer Consortium (DKTK)
niversity Hospital Essen