Targeted Re-engineering of the Tumor Matrix to Advance Immunotherapy

Immunotherapy can prolong lives of cancer patient subgroups, but fails in solid tumors with dense fibrotic stroma, such as pancreatic cancer.

Fibrotic stroma prevents the recruitment and activation of immune effector cells, and, thereby dampens the efficacy of immunotherapy.

Mechanistically, cancer-associated fibroblasts (CAFs) initiate extracellular matrix (ECM) production, which aggravates fibrosis by reciprocal mechanoactivation and crosstalk with tumor-associated myeloid cells, forming a self-sustainable “pro-fibrotic loop”.

However, the central pathways initiating this vicious cycle and signaling compensation maintaining fibrosis under therapeutic conditions remain unclear.

Consequently, clinical solutions to disrupt this pro-fibrotic loop are lacking.I hypothesize that identifying and targeting the multi-step pro-fibrotic loop can be exploited to re-engineer and normalize the perturbed ECM and increase tumor accessibility for immune effector cells and immunotherapy.To disrupt the pro-fibrotic loop, I will exploit an engineered modular peptido-/nanobio-mimetic toolbox, comprising nature-inspired targeting systems based on in silico design and experimental validation.

The peptidomimetics and nano-biomimetics will target cellular interaction mechanisms to (1) inhibit CAF–ECM interactions driving tissue stiffening and fibrosis, and (2) train tumor myeloid cells towards matrix-degrading effectors to restructure fibrotic ECM. These biomimetics will be examined in advanced 3D in vitro and in vivo pancreatic tumor models.

The combined effects of biomimetics on the matrisome, matrix architecture and single-cell transcriptomics will be integrated using machine learning to identify ECM fingerprints.

OpenMatrix will 1) deliver mechanistic insights into endogenous fibrosis drivers and antagonists, 2) engage these cell-intrinsic mechanisms to revert fibrosis and, thereby, 3) reactivate immune effector function and advance immunotherapy.