Disruption of systemic and microenvironmental barriers to immunotherapy of antigenic tumors

Descripción del proyecto

Eliminar los obstáculos para una inmunoterapia eficaz contra el cáncer

Durante las últimas décadas, se han probado multitud de inmunoterapias nuevas contra el cáncer y se han descubierto distintas maneras de activar el sistema inmunitario. Sin embargo, diversos tipos de cáncer no responden a estos tratamientos nuevos. Los mecanismos de resistencia adaptativa y preexistentes evitan la activación de los linfocitos T citotóxicos capaces de infiltrarse en los tumores sólidos y eliminar las células cancerosas. El proyecto financiado con fondos europeos CAN-IT-BARRIERS reunirá conocimientos nuevos sobre los obstáculos sistémicos y microambientales a la inmunoterapia en los cánceres resistentes con el fin de evaluar el potencial terapéutico de estrategias diseñadas para eliminar dichos obstáculos. La investigación se centrará en cómo los queratinocitos que expresan oncogenes provocan una expansión de células mieloides inmunodepresoras en el bazo y los ganglios linfáticos, así como en la manera en que estas células inhiben el desarrollo y la activación de linfocitos T citotóxicos y células dendríticas presentadoras de antígenos.

Objetivo

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.