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Converting pro-tumour macrophages into cancer killers

Epithelial cancers, such as cancers of the lung and pancreas, use the ανβ3 molecule to gain drug resistance to standard cancer therapies and to become highly metastatic.

In a paper published in Cancer Research, University of California San Diego School of Medicine researchers identified a new therapeutic approach in mouse models that halts drug resistance and progression by using a monoclonal antibody that induces the immune system to seek and kill ανβ3-expressing cancer cells.

"This antibody is designed to seek and destroy the most stem-like, drug-resistant, aggressive tumour cells. It does this by building a bridge between tumour-associated macrophages and these highly aggressive tumour cells," said David Cheresh, PhD, Distinguished Professor and vice chair of Pathology. "What we have been able to observe in mice is that when we give this drug to drug-resistant tumours, it prolongs their response to standard of care and prevents their capacity to enter the blood stream."

Using the ανβ3 antibody LM609, Cheresh and his team exploited the appearance of ανβ3 receptors on tumour cells to redirect tumour-associated macrophages (TAMs) into recognising and killing ανβ3 expressing tumour cells.

During the study period, no tumour progression or drug resistance was detected while untreated animals developed tumour growth and metastasis.

"The research in mouse models focused on pancreatic and lung cancer cells treated in combination with LM609 and the EGFR inhibitor erlotinib. But, the antibody is expected to work in combination with various drugs currently used to treat cancer patients," said Cheresh.

"We have observed a highly significant link between the appearance of ανβ3 expressing tumours and the appearance of tumour-associated macrophages," said Cheresh, associate director of innovation and industry alliances at UC San Diego Moores Cancer Center. "Normally, the appearance of tumour-associated macrophages promotes tumour growth and metastasis. However, our antibody arms these macrophages to join our fight against the cancer."

Macrophages are specialised immune cells that promote tissue inflammation, stimulate the immune system and rid the body of foreign debris, including cancer cells.

TAMs instead create a pro-tumour environment that accelerates tumour growth, angiogenesis (the development of new blood vessels to support the tumour) and suppresses immune recognition of the tumour by the host immune response.

As tumours progress, the abundance of TAMs increases, allowing the cancer to become more aggressive and spread.

As tumours become drug-resistant, ανβ3 appears on cell surfaces.

The Cheresh lab previously discovered that ανβ3 is up-regulated on various cells during normal wound repair and in cancer cells as cancer becomes invasive.

In both cases, this molecule triggers cells to enter a stress-tolerant state.

In normal epithelial cells, this state enables them to initiate tissue remodelling, such as healing.

In cancer, it allows cells to become drug-resistant and highly metastatic.

The current study revealed a new approach to induce TAMs to reverse course, killing cancer cells rather than supporting them.

The antibody prompts these macrophages to begin killing tumour cells through a mechanism known as antibody-dependent cytotoxicity (ADCC).

"These results were initially unexpected since macrophages usually destroy cells via phagocytosis, a process that involves them literally devouring the foreign or target cell," said Cheresh, a faculty member of the Sanford Consortium for Regenerative Medicine. "Also, ADCC is typically known to be induced by natural killer cells, but we saw very few of these NK cells in the late-stage, drug-resistant cancers we have examined."

"We believe that the effectiveness of this antibody is based on three things: Its capacity to recognise drug-resistant cancers. Its ability to bind to a particular receptor on tumour-associated macrophages. And its capacity to induce ADCC of these highly aggressive tumour cells," added Cheresh.

The protein CD47, which is found on many cells in the body and is often hijacked by cancer cells, tells macrophages not to eat these cells.

The ανβ3 antibody bypasses the CD47 "don't eat me signal" by inducing ADCC as opposed to phagocytosis.

"In our studies, macrophages are not killing through phagocytosis which would be blocked by the appearance of CD47 on the tumour cell target. Rather, we're inducing macrophage to kill its tumour cell target by its ability to mediate ADCC. The therapeutic antibody we are utilising is bridging the macrophage to the ανβ3-expressing tumour cell as a target. When this occurs it releases a cytotoxic substance that kills the tumour cell," explained Cheresh. 

The team is currently producing a humanised version of this antibody, which Cheresh hopes will do in humans what LM609 does in mice.

Source: University of California - San Diego

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