Immune interactions in the tumor microenvironment

The tumor microenvironment involves a complex interplay between different types of immune, cancer and stromal cells, which can lead to either tumor growth-suppression or to tumor progression and invasion. While the majority of immune cell types in the TME have been identified and at least partially characterized, their mutual interactions and communication, and the sequential effect of these immune interactions on shaping the microenvironment composition and controlling tumor growth is largely unknown. This uncharted web of interactions is the focus of our studies. We use spatial multi-omics approaches such as advanced multiplex imaging coupled with transcriptomic immune profiling to analyze the spatial tumor architecture. We are studying which immune cell interactions inside the tumor define the outcome of effective or defective antitumor immunosurveillance and response to immunotherapy, and the mechanisms of their interactions. Furthermore, we apply a research-to-therapy approach to identify immune-immune and tumor-immune interactions that are valuable as therapeutic targets, utilizing advanced antibody-engineering to develop unique new approaches to potentiate anti-tumor immunity.

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Bispecific immune Cell Engager (BiCE): Our new platform to engineer immune cell communication for cancer immunotherapy. 
Immune checkpoint inhibition treatment using aPD-1 monoclonal antibodies is a promising cancer immunotherapy approach. However, its effect on tumor immunity is narrow, as most patients do not respond to the treatment or suffer from recurrence. In our recent study, we show that the crosstalk between conventional type I dendritic cells (cDC1) and T cells is essential for an effective aPD-1-mediated anti-tumor response. Accordingly, we developed a bispecific DC-T cell engager (BiCE), a reagent that facilitates physical interactions between PD-1+ T cells and cDC1. BiCE treatment promotes the formation of active dendritic/T cell crosstalk in the tumor and tumor-draining lymph nodes. In vivo, single-cell and physical interacting cell analysis demonstrates the distinct and superior immune reprogramming of the tumors and tumor-draining lymph nodes treated with BiCE as compared to conventional aPD-1 treatment. By bridging immune cells, BiCE potentiates cell circuits and reignites immune cell communication pathways needed for effective anti-tumor immunity.


Shapir et al. Cell, 2024.