Reviewing the diverse roles of pattern recognition receptors in cancer

Professor Si Ming Man. Image: Lannon Harley/ANU
31 March 2022

By the time you finish reading this article, your immune system would have likely wiped out a few individual cancers cells hidden somewhere in your body.

Indeed, no matter how scary the term “cancer cells” may sound to many of us, it’s but one of many types of threats our immune system has to deal with every day. From initiation to metastasis, the immune system has roles to play in all facets of cancer.

Most of the time, our immune cells can detect and eliminate emerging cancer cells before they cause any harm to the body. But in a few cases, cancer cells can evolve to outsmart the immune system, hiding from the latter’s surveillance and even tricking it into helping them thrive.

Researchers are striving for understanding what the immune system undergoes in different oncology settings to find ways of helping it turn the tide of the battle against cancer.

Previous research on adaptive immunity has enabled the employment of immune checkpoint inhibitors as immunotherapy, for example, to treat numerous cancers, yielding varying degrees of success.

While research interests in the role of the other arm of the immune system—innate immunity—in cancer have not yet led to approved therapeutics for cancer patients, the landscape is evolving rapidly with some exciting discoveries.

In a new review article published in Nature Reviews Cancer, Professor Si Ming Man at The John Curtin School of Medical Research and Professor Brendan Jenkins at Hudson Institute of Medical Research provided a comprehensive overview of the role of a critical class of innate immune sensors called pattern recognition receptors (PRRs) in cancer.

The article had a contextualised look at the contribution of different PRRs to various tumour-inhibiting and tumour-promoting cellular responses and discussed the potential of PRRs-targeting cancer therapeutics.

“There is no doubt the immune system helps us fight cancer, so it’s an exciting time to think about how to harness the power of PRRs better,” says Professor Man, “This article discusses the current state of affairs and what it means for the treatment of patients with cancer in the future.”  

PRRs are germ-line encoded innate immune sensors that detect infection and tissue damage in our bodies. 

Studies in the past decade have suggested the involvement of PRRs in virtually every solid and liquid cancer type. In both immune and non-immune cells, these receptors coordinate orchestrate tumour-inhibiting and tumour-promoting processes that shape the fate of cancer. 

For instance, evidence has shown that Toll-like receptor 2 (TLR2), a membrane-bound PRR, exhibits a tumour-promoting role in supporting metastatic growth of advanced tumours via its increased expression and activation in innate immune cells such as macrophages and neutrophils. Meanwhile, TLR2 deficiency leads to increased sensitivity in mice to several carcinomas, suggesting a tumour inhibitory function of the receptor.

By scrutinising the complicated, often opposing functions that different PRRs display in diverse cells during distinct stages of various cancers, the authors highlighted the unprecedented opportunity to develop anti-cancer therapeutics targeting the activation of PRRs. Strategies can be developed focusing on either augmenting the tumour-inhibiting properties of PRRs or suppressing their tumour-promoting ones.

Nevertheless, the complex landscape of PRR-driven signalling pathways in cancer also emphasises “the need for caution when evaluating the potential clinical implementation of specific PRR antagonists or agonists in individual cancer settings”, wrote the authors.

Ongoing research in the Man Group is to understand why two PRRs called Ku70 and NLRC4 are dysfunctional in patients with colorectal (bowel) cancer. They show that a failure in these PRRs leads to more tumour growth. Now, they are working on ways to boost the activity of these PRRs to slow down or even block cancer development.