A team of Portuguese researchers has uncovered an unexpected cellular cross-talk behind ovarian cancer growth, that can be used as a therapeutic target for future immuno-oncology strategies. The research is particularly interesting because it reveals that the normally anti-tumour gd T lymphocytes (a type of white blood cells) can also be pro-tumour.
Ovarian cancer is the seventh cause of death among women worldwide, with the number of women diagnosed every day reaching 19 in the UK and 60 in the US. The new work, which will be published in the journal PNAS, was led by Bruno Silva-Santos from the Instituto de Medicina Molecular (IMM), Faculdade de Medicina da Universidade de Lisboa, Portugal.
It is known that the development of solid cancers is influenced by multiple white blood cell subsets that can inhibit or, paradoxically, promote tumour cell growth. But gd T lymphocytes until very recently were seen as a clear part of the immune response against cancer by producing IFNgamma, a well-known anti-inflammatory and anti-cancerogenous protein.
In fact, it was even shown, in several cancer models, that gd T lymphocytes infiltrated tumors very early significantly delaying their growth. This triggered multiple lines of research, by groups all over the world, to exploit γδ T cells anti-tumour capabilities for cancer immunotherapy with highly promising results.
But, too much surprise, a 2012 clinical study on breast cancer tissue unexpectedly revealed an inverse correlation between infiltrating γδ T cells and overall patient survival. In fact, in this study γδ T cells represented the most significant independent prognostic factor for assessing severity of breast cancer (so they directly correlated with disease severity)
And now the new study by PhD student Margarida Rei, in collaboration with colleagues from Queen Mary University of London (UK), gives support to this alternative role of gd T lymphocytes, as the researchers describe a cellular cross-talk, mediated by the pro-inflammatory protein IL-17 (IL-17), between these lymphocytes and small peritoneal macrophages (SPM) that stimulates ovarian cancer growth in the peritoneal cavity.
"Our work characterizes a new cellular axis involving gd T lymphocytes, IL-17 and SPM, which promotes tumour development. As such, the neutralization of this pro-tumour axis offers new therapeutic targets aiming to inhibit cancer growth in the clinic", underlines Bruno Silva-Santos.
So the big difference in these results is that gd T lymphocytes are producing IL17 (pro-inflammatory protein) instead of IFNgamma (anti-inflammatory and anti-cancerogenous protein).
"The key molecule, IL-17, is preferentially produced by a specific population of gd T lymphocytes which expand as the tumour grows, and this associates with the recruitment of SPM macrophages, which in turn express pro-tumour and pro-angiogenic mediators induced by IL-17 itself", continues Bruno Silva-Santos: "These SPM are thus capable of directly promoting ovarian cancer cell growth."
Ovarian cancer in Portugal has one of the lowest incidences in Europe, and yet is still diagnosed in more than 5 women, killing more than 3, in 100.000 every year. Worldwide, just in 2012 almost 250 thousand women were diagnosed with the disease with disease rates varying between different countries. For example, in 2012 the US had more than 22 thousand new diagnosed cases and 14 thousand deaths.