Myeloid Cells: Investigating their Role for Immunotherapy in Cancer

Descripción del proyecto

Implicación de las células dendríticas en la inmunoterapia

La activación del sistema inmunitario para combatir el cáncer es una estrategia prometedora que, sin embargo, ha demostrado tener una eficacia limitada en la práctica clínica. Para mejorar los resultados de la inmunoterapia, los científicos del proyecto financiado con fondos europeos MIRIC proponen emplear células mieloides, como las células dendríticas, que desempeñan un papel clave en las respuestas de los linfocitos T específicos de antígenos y el pronóstico del cáncer. MIRIC se centrará en la inmunoglobulina de linfocitos T y el dominio 3 de mucina (TIM-3), un punto de control inmunitario responsable del agotamiento de los linfocitos T y la inhibición de la inmunidad antitumoral. Mediante el uso de tecnologías ómicas y un método de inmunología de sistemas, el equipo del proyecto descifrará los resultados de la modulación de TIM-3 en el cáncer, a la espera de arrojar luz sobre los factores que rigen las respuestas inmunitarias en las neoplasias malignas.

Objetivo

With more than 3.7 million new cases and 1.9 million deaths each year, cancer represents the second most important cause of death and morbidity in Europe with the estimated direct health cost increasing from €79 to €86 billion during 2005-2014. The emerging field of immune-checkpoint therapy (ICT) has demonstrated unprecedented responses in patients with several types of metastatic tumors that were previously resistant to available treatment options. However only ~13% of patients respond to the immunotherapy. I believe the primary reason for this is that most therapies are T cell directed and to achieve durable responses one must also engage the innate arm of the immune system. Myeloid cells constitute a major proportion of tumor infiltrating cells in human cancers and are essential for the induction of antigen specific T cell responses-cells which mediate anti-tumor immunity. Tim-3 is a check-point molecule that is not only expressed on T cells but also constitutively expressed on Dendritic cells, namely DC1, which are particularly adept at initiating protective anti-tumour immunity. A number of studies have highlighted the crucial role of DCs including analyses of The Cancer Genome Atlas showing that patient survival for many cancers correlates positively with the gene expression signature for DCs. Given the current activity in developing Tim-3 blocking agents for clinical translation, it is imperative that we have a full understanding of how modulation of Tim-3 affects the innate arm of the immune system. The aim of this proposal is to determine the cell-intrinsic and non cell-intrinsic effects of Tim-3 modulation in cancer. Furthermore we will analyze the cellular and transcriptional changes associated with tumour infiltrating DC after ICT with anti-Tim3. This proposal is highly interdisciplinary implementing single-cell 'omics' strategies and systems immunology approaches to further unravel the players and rules governing immune responses during malignancy.