Roche-backed researchers find a way to lure back immune system from cancer’s grasp

Lab work

Cancer cells have a nasty capacity to steer the body’s immune system to actually help them grow, stopping a key defense against cancer development--but researchers have now found a way to recruit the immune system back to its native side.

Writing in the journal Natural Cell Biology, researchers from École Polytechnique Federale de Lausanne (EPFL) say they have now found a way to reclaim the corrupted immune cells, turn them into signals for the immune system to attack the tumor, and even prevent cancer spreading.

The Roche ($RHHBY)-partnered study used a very early-stage bioinformatics approach to show how macrophages--cells of the immune system that protect the host from invading pathogens--can be brought back into the fight against cancer after being "hijacked" by tumors, where they are made to support their malignant growth and spread.

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EPFL scientists, working with colleagues at the Roche Innovation Centers in Munich and Basel, have now identified a molecular "switch" that can convert the hijacked macrophages into cells that can stimulate the immune system to fight tumors.

When a tumor begins to develop, macrophages attempt to block its growth. But often tumors hijack them and convert them into what are known as "tumor-associated macrophages," or TAMs.

Now corrupted, TAMs use their microRNAs to shield the tumor from the patient's immune system, helping it grow and metastasize. This phenomenon is common across many tumor types. It is one of the major obstacles in treating cancer, and often leads to a poor prognosis for the patient.

Michele De Palma's team at EPFL found how to reclaim TAMs. The researchers genetically modified TAMs to remove their ability to produce microRNAs. As a result, the TAMs were reprogrammed. Instead of protecting the tumor, the TAMs now signaled the presence of the tumor to the immune system, triggering attacks against it.

Using a bioinformatics approach, the researchers found that the most likely culprit was a small family of microRNAs, called Let-7. This offers a more specific target: Blocking Let-7 microRNAs may help instruct the TAMs to stimulate anti-tumor immunity.

The researchers observed that reprogramming TAMs also stops cancer cells from leaving the primary tumor. This could mean that the approach can also prevent tumor metastasis, the authors said.

Moreover, the researchers found that the re-educated TAMs could enhance the anti-tumoral efficacy of certain cancer immunotherapies--some of which are already approved for patients.

However, the authors note that much more work is needed to translate all these findings to actual therapies--especially since there is currently no way to block the Let-7 microRNAs selectively in TAMs. But De Palma's lab is now working with bioengineers at EPFL to design drugs that can target the Let-7 microRNAs specifically in the TAMs.

Some of the most recent promising cancer treatments are immunotherapies, which are based on provoking or enhancing the patient's immune response against their tumor, with Bristol-Myers Squibb ($BMY) and Merck ($MRK) currently leading this new field with their checkpoint inhibitors Opdivo and Keytruda, respectively. Roche also recently became the third company to gain approval for its checkpoint inhibitor Tecentriq for a type of bladder cancer.

“The most exciting finding was that TAM reprogramming greatly improved the efficacy of immunotherapy,” says Michele De Palma. “Our results in experimental models of cancer suggest a new therapeutic strategy based on inhibiting the microRNA machinery--or the Let-7 microRNAs--specifically in the TAMs, which may unleash the power of mainstream immunotherapies, such as immune checkpoint inhibitors.”

The study involved a collaboration of EPFL's Swiss Institute for Experimental Cancer Research with the Roche Centers for Innovation at Basel and Munich and was funded by the Swiss National Science Foundation, the Fondation pour la lutte contre le cancer, the Swiss Federal Commission for Scholarships for Foreign Students and Roche.

- check out the paper