Publication highlights

This important paper showed very high levels of infection amongst healthcare workers in a local hospital. It has influenced government policy – asymptomatic healthcare workers are to be screened as per our recommendation (announced October 12th).

Conventional dendritic cells (cDCs) originate from a committed precursor in bone marrow (BM) that exits via the blood as a pre-cDC to seed tissues with the cDC1 and cDC2 subsets. We used a multi-colour genetic tracing mouse model to analyse colonisation of tissues by pre-cDC. We found that cDCs in tissues comprise clones mostly composed of a single cDC subset and that ‘flu infection causes an efflux of pre-cDCs from BM and influx into the lungs. The latter finding indicates that cDCpoiesis is responsive to emergency need, which suggests previously undiscovered communication between tissues and cDC progenitors in BM.

In this paper we showed that cDC1 recruitment and infiltration in several mouse tumour models depends on the chemokines CCL5 and XCL1 produced by NK cells. In human cancers, CCL5/XCL chemokine transcripts correlate with gene signatures for NK cells and cDC1 and predict overall survival in melanoma, head and neck cancer, breast cancer and lung adenocarcinoma. Therefore, our data uncovered a mechanism for cDC1 recruitment into tumours that is translatable to humans and cancer patient survival.

In this paper, we uncovered a potent mechanism of cancer immune evasion, namely cyclooxygenase (COX)-dependent secretion of prostaglandin E2 (PGE2) by tumour cells. We further showed that the growth of PGE2-secreting tumours in mice can be reversed by a combination of checkpoint blockade immunotherapy and COX inhibitors, suggesting that COX inhibition might be a useful addition to both conventional and immune-based therapy of cancer. This paper led to seven clinical trials worldwide to test combinations of prostaglandin E2 inhibition with checkpoint blockade cancer therapies.

Our previous work showed how stromal fibroblasts lead the collective invasion of cancer cells, and documented how remodelling of the extracellular matrix was important for this behaviour. Following our observation of direct cell-cell contacts between cancer cells and fibroblasts, we hypothesised that the two cells might be mechanically coupled; therefore, we began collaborating with Xavi Trepat (IBEC Barcelona), who is a world leader in the mechanics of multi-cellular systems. By biophysical measurements and a range of conventional cell and molecular biology manipulations, we demonstrated that fibroblasts actively ‘pull’ cancer cells into the surrounding extracellular matrix.

In this study, we used our bank of patient-dervied stromal fibroblasts to ask why some fibroblasts generate highly aligned extra-cellular matrices and other do not. We were able to show how cell migration and cell-cell collisions can dictate the patterns formed by fibroblasts, and that furthermore, the higher order organisation of fibroblasts and matrix is associated with millimetre scale contraction of reconstituted tissues and cancer invasion. The quantitative tool developed during the course of this work and a related study is now being tested for its prognostic value in simple histological stains of breast and prostate cancers.

We set up a complex model for lung alveoli by co-culturing lung fibroblasts and alveolar epithelial type I and type II cells on a gas permeable support, with the expectation that the fibroblasts would strongly influence the behaviour of cancer cells introduced into the system. However, we discovered that the largest effect came from the alveolar epithelial cells, and we then used a range of approaches to delineate the signalling mechanisms involved. This work, together with a concomitant study from the Malanchi group, established the role of epithelial cells in the tumour microenvironment of indolent and micro-metastases.

This work shows why stromal fibroblasts are an important source of inflammatory modulators in tumours. We show fibroblasts can respond to cGAMP produced by cancer cells, but only when the two cell types are in direct contact. This in turn promotes the STING and IRF3 dependent expression of interferon beta and various chemokines. The subsequent up-regulation of interferon-stimulated gene expression undermines the efficacy of oncolytic viruses. We propose the requirement for direct contact represents a ‘tissue level’ mechanism for triggering this response specifically in the context of tissue damage, as in healthy tissue, the basement membrane precludes such interactions.