A team has built miniature 3D models of human tumours—complete with blood vessels and immune cells—to test why most cancers resist immunotherapy. These lab-grown models mimic the dense, suppressive environment that tumours create around themselves, including the stiff extra-cellular matrix and tumour-promoting immune cells that block killer T-cells from reaching malignant cells. Currently, only a minority of patients benefit from immunotherapies. The researchers will use microfluidic chips to vascularise the models, then watch how engineered CAR-T cells and gamma delta lymphocytes try to penetrate and kill the tumour. They will also test ways to “remodel” the tumour microenvironment—softening the matrix or reprogramming the immune cells—to make cancers vulnerable to attack. If successful, this work could transform how new immunotherapies are tested before reaching patients, replacing some animal experiments with faster, more human-relevant systems. The ultimate goal is to shift the balance so that a majority, not a minority, of cancer patients respond to immune-based treatments.
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The aim of this project is to harness novel human multicellular models of the tumour microenvironment that I and my team have recently developed, to answer critical questions in cancer biology and immunotherapy. With my extensive data resource from ovarian cancer patient biopsies as a foundation and validation, I will integrate state-of-the-art single cell and multiplex analyses of these models to define the influence of malignant cells and host fibroblasts on tumour microenvironment composition, vascularise the models in microfluidic systems to define barriers to CAR-T and gamma delta lymphocyte cytotoxicity, and discover the best ways to REMODEL cancers to enhance immune cell killing. While it is clear that the immune system has the power, complexity and specificity to destroy evolving malignant cell clones, there are many obstacles in its way. These include changes to the extra-cellular matrix that deter interactions of certain immune cells with malignant cells, as well as cells and mediators of the immune system that out-manoeuvre the host anti-tumour response. Our human multi-cellular models produce extra-cellular matrix proteins associated with immune suppressive pathways and contain myeloid cells that have markers in common with tumour-promoting macrophages. The models offer the flexibility, reproducibility and speed to find best ways to target these barriers to anti-cancer immunity. My vision is that this ground-breaking project will take complex 3D in vitro human cell models to new levels of analysis, output and usefulness, testing them against in vivo and ex vivo models in ways that will accelerate and improve pre-clinical testing of immuneand other cancer therapies and reduce/refine the use of animals. A minority of patients currently benefit from immunotherapies. Remodelling cancer microenvironments to improve immune cell killing of malignant cells can change this to a majority.
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