ABSTRACT

Title: Beyond the cancer cell: Exploring the tumour stroma as immune modulators

Summary: Current immunotherapy approaches show great promise but are effective in just a few cancer types.

Therefore, a clear knowledge deficit exists in our understanding of anti-tumour immunity and the suppressive networks at play during the different stages of malignant transition.

Surveillance by the immune system has been implicated as a major barrier to the progression of early cancers, however, tumours have developed strategies to interfere with almost every step necessary for an effective anti-tumour immune response.

“Normal” cells termed the stroma in surrounding tissue – including fibroblasts, endothelial cells, pericytes and immune cells – form a tumour microenvironment that co-evolves with cancer from its earliest stages to shape progression, and mounting evidence indicates that components of the stroma support immune suppression to promote carcinogenesis via mechanisms that remain poorly understood.
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We have demonstrated that the fibroblast compartment of stroma is a key modulator of both the innate and adaptive arms of the anti-tumour immune response at local and systemic levels; directly inducing antigen-specific antigen-dependent deletion of tumour-reactive T cells and stimulating the recruitment of neutrophils to drive formation of neutrophil extracellular traps in an amyloid beta-depndent manner.

Using single cell RNA sequencing we have been able to show that cancer-associated fibroblasts (CAF) and accompanying immune cells adapt to meet the changing requirement of a tumour showing the existence of temporally distinct CAF populations displaying distinct functional signatures to indicate that even from early stages of carcinogenesis, cancer associated fibroblasts possess the capacity to drive the tumour immune landscape towards a suppressive phenotype

In summary, we have described both direct and indirect mechanisms by which the tumour stroma can help shape the development of an immune dysfunctional environment that ultimately supports tumour growth.