Cellular network identified that 'short circuits' immunotherapies

13 Nov 2017

Researchers have discovered a novel form of crosstalk among tumour cells and other cell types in the tumour microenvironment, elucidating the mechanism of action of an immunotherapeutic strategy that inhibits tumour-associated macrophages (TAMs) and instructing a more effective use of this therapeutic approach.

This work was published online in Cancer Cell.

TAMs make up a prominent immune cell population present in the tumour microenvironment.

Because of their ability to promote tumour cell proliferation and invasion and inhibit antitumor immune response mediated by T cells, TAMs are considered a potential therapeutic target. Inhibition of the CSF-1 receptor (CSF-1R), which mediates the functions and survival of TAMs, has received interest as a potential strategy to eliminate these cells.

However, despite being effective at depleting the TAMs in various tumour models, this strategy has failed to achieve the expected antitumour effects.

"Our findings revealed new aspects of the intricate cellular network that involves tumor cells, TAMs and cancer associated fibroblasts that talk to each other via production of chemical messengers," said Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and program leader of the Immunology, Microenvironment and Metastasis Program at The Wistar Institute. "We discovered an additional effect of CSF-1R inhibition that brings into play other immunosuppressive cells that sustain tumour progression."

Gabrilovich and colleagues found that, besides depleting TAMs from the tumour site, CSF-1R inhibition also resulted in the unexpected recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which favour tumour progression and mediate resistance to immunotherapy approaches.

The presence of these cells may explain the lack of antitumor effect by CSF1R inhibition.

The researchers investigated the mechanism of PMN-MDSC recruitment to the tumour site and uncovered an intricate crosstalk that resulted in increased production of signalling proteins responsible for attracting PMN-MDSCs in response to CSF-1R inhibition.

In particular, they observed higher levels of Cxcl-1, in this context produced by cancer-associated fibroblasts.

"In order to achieve a therapeutic effect, we realized that we needed to reduce the presence of both immunosuppressive populations, TAM and PMN-MDSC," added Gabrilovich.

By combining the CSF-1R inhibitor with a selective inhibitor of CXCR2, which is the receptor for Cxcl-1 and other molecules whose levels are increased as a consequence of CSF-1R inhibition, they observed significant reduction in tumour growth.

In addition, the combination of the two inhibitors together with an immune checkpoint inhibitor resulted in a dramatic antitumor effect, providing additional therapeutic benefits.

Source: The Wistar Institute