Chemotaxis in Cancer

Principal investigator: GUIDO KROEMER
www.kroemerlab.com

Explaining the heterogeneity of the immune infiltrate

Tumors are heterogeneous in the composition of their immune infiltrate, a fact that is clinically relevant. Infiltration by specific immune cell subtypes positively impacts patient survival, while suppressive cells have a negative impact. Cancers without immune infiltration (“cold tumors”) at diagnosis fail to respond to any kind of therapy and, conversely, some kinds of chemotherapy stimulate immune infiltration. Leukocyte infiltration is dictated by chemotactic factors, most of which are initially produced by malignant cells and later can be generated by immune and stromal cell subpopulations as well. Chemotaxis in cancer teams work to dissect the heterogeneity of the immune infiltrate by analyzing intensity, spatial arrangement and functional characteristics of the relationship between malignant and immune cells determined by chemotactic factors.

Equilibrium between immune cells & tumoral cells

The network is interested in identification of chemotactic factors and receptors affecting the immune infiltrate in tumors. With partners’ in–house collections of human tumors, loss of function mutations of chemokines or chemokine receptors and detectable chemotactic factors in tumors (at mRNA and proteins level) are characterized. Chemotactic factors are also studied from freshly explanted cancers. Correlations with public and generated data (ligands vs. receptors vs. immune parameters vs. clinic-biological characteristics) is performed by the network.

In sito technology (in situ + in vivo = in sito)

Moreover, network partners used multistaining immunohistochemical (LC3B, ANXA1, chemokines; immune cell types) to measure spatial arrangements of local producers of chemotactic factors (from malignant or stromal cells) and immune effectors. They also study the dynamic relationship between malignant and immune cells by various approaches. Firstly, Laurence Zitvogel team developed an “in sitro” technology from fresh tumor. This new methodology published recently by the team (Nat Commun. 2017; 8: 592) consist in preparation of a cells suspension from a fresh tumor, performed experimentations (treatment, depletion,…) and analyze by different methods (mRNA, flow cytometry, cytokine detection) cells reactivity, interaction and supernatant.

Study of dynamic relationship between malignant & immune cells with the Immuno-Oncology Chip (IOC)

Secondly, ex vivo experimentations are performed with fresh tumor slices cultured in vitro, under video-microscopic observation after addition of fluorescent-labelled immune cells. Thirdly, some partners are developing a microfluidic device coupled with fluorescence video-microscopy called Immuno-Oncology Chip (IOC) that will allow to visualize dynamic between malignant cells, immune cells in various conditions.

By the combination of systems biology methods, sophisticated ex vivo and in vitro culture techniques, Chemotaxis in cancer network anticipate furnishing an explanation for the heterogeneity of the immune infiltrate. They also aim to yield prognostic and predictive biomarkers. Moreover, they are trying to unravel novel therapeutic strategies like the conversion of cold into hot tumors, by identification of intervention points.

This French program is organized by ITMO Cancer, in collaboration with ITMO BCDE (Cell Biology, Development and Evolution) and ITMO Technologies for Health of the National Alliance for Life Sciences and Health (AVIESAN) with the National Cancer Institute (INCA) and Inserm within the framework of the Cancer Plan. Operational management is entrusted to Inserm.
It was launch in order to develop a critical mass of resources and skills in order to conduct interdisciplinary research projects in the field of functional heterogeneity of cellular tumor relations in their ecosystem: the "HTE Program".

Initiation of HTE Program