Disruption of systemic and microenvironmental barriers to immunotherapy of antigenic tumors

Projektbeschreibung

Hindernisse effizienter Krebsimmuntherapie beseitigen

In den vergangenen Jahrzehnten sind neue immuntherapeutische Behandlungen gegen Krebs getestet und neue Möglichkeiten zur Aktivierung des Immunsystems in rasantem Tempo entdeckt worden. Viele Krebsarten sprechen jedoch nicht auf diese neuen Therapien an. Bereits bestehende und adaptive Resistenzmechanismen verhindern die Aktivierung der tumorreaktiven zytotoxischen T-Zellen, die solide Tumoren infiltrieren und Krebszellen beseitigen können. Das Ziel des EU-finanzierten Projekts CAN-IT-BARRIERS ist es, neue Erkenntnisse über die Hindernisse im System und in der Mikroumgebung für die Immuntherapie bei refraktären Krebserkrankungen zu gewinnen und so das therapeutische Potenzial von Strategien zur Beseitigung dieser Hindernisse zu beurteilen. Der Schwerpunkt der Forschung wird darin bestehen, herauszufinden, wie Onkogen exprimierende Keratinozyten eine Expansion immunsuppressiver myeloider Zellen in Milz und Lymphknoten auslösen und wie diese Zellen die Entwicklung und Aktivierung von CD8-T-Zellen und antigenpräsentierenden dendritischen Zellen hemmen.

Ziel

The frontier in cancer therapy of orchestrating the immune system to attack tumors is producing unprecedented survival benefit in some patients. The corollary is lack of efficacy both in ostensibly responsive tumor types as well as others that are mostly non-responsive. The basis lies in pre-existing and adaptive resistance mechanisms that circumvent induction of tumor-reactive cytotoxic T cells (CTLs) capable of infiltrating solid tumors and eliminating cancer cells. A priori, cancers induced by expression of human papillomavirus oncogenes should be responsive to immunotherapy: these cancers encode immunogenic neo-antigens – the oncoproteins E6/7 – necessary for their manifestation. Rather, such tumors are poorly responsive to immunotherapies. Results from my lab and others using mouse models of HPV-induced cancer have established an actionable hypothesis: during tumorigenesis, such tumors erect multiple barriers to the induction, infiltration, and killing of cancer cells by tumor antigen-reactive CTLs. These include overarching systemic antigen-nonspecific immunosuppression mediated by expanded populations of myeloid cells in spleen and lymph nodes, complemented by immune response-impairing barriers operative in the tumor microenvironment. A spectrum of models will probe these barriers, genetically and pharmacologically, establishing their functional importance, alone and in concert. A major focus will be on how oncogene-expressing keratinocytes elicit a marked expansion of immunosuppressive myeloid cells in spleen and lymph nodes, and how these myeloid cells in turn inhibit development and activation of CD8 T cells and antigen-presenting dendritic cells. Then we’ll assess the therapeutic potential of barrier-breaking strategies combined with immuno-stimulatory modalities. This project will deliver new knowledge about multi-faceted barriers to immunotherapy in these refractory cancers, helping lay the groundwork for efficacious immunotherapy.