Abstract
An antibody drug directed at the collagen receptor DDR1 helps to mitigate immune exclusion in a mouse model of triple-negative breast cancer, allowing T cells to flood in and slow tumor progression. A startup company called Parthenon Therapeutics has launched to advance the therapy into clinical development.
Tumors shield themselves from immune attack by constructing protective barriers of collagen. But this defense mechanism can be circumvented through blockade of the collagen receptor DDR1, allowing for cancer-killing T cells to flood in and slow tumor progression.
The findings, from a mouse model of breast cancer, suggest that therapeutically targeting DDR1 could help overcome a key mechanism of immune exclusion, a trait common to many solid tumors that has been linked to poor survival (Nature 2021 Nov 3 [Epub ahead of print]).
In the new study, a team co-led by Rong Li, PhD, of George Washington University in Washington, DC, and Zhiqiang An, PhD, of the University of Texas Health Science Center at Houston, showed that the outer segment of DDR1 helps to align collagen fibers in the extracellular matrix surrounding cancers. This creates fencing akin to barbed wire around tumors that keeps T cells at bay.
In mice, genetic removal of DDR1 from tumors disrupted the patterning of collagen, leading to enhanced immune infiltration and reduced tumor growth. Antibody drugs directed at DDR1's outer domain had the same effect.
The researchers focused their efforts on models of triple-negative breast cancer—and they have human data to suggest the findings should have clinical relevance. In women with this aggressive malignancy, the researchers showed that higher expression of DDR1 in tumor samples correlated with greater exclusion of anticancer T cells.
However, Li anticipates that DDR1 blockade should be an effective way of modulating the immune milieu in a variety of different tumors. “Immune exclusion is a pan-cancer phenotype,” he says, so “the same strategy could be applied to other cancer types.”
Shaan Gandhi, MD, DPhil, director of Northpond Ventures in Cambridge, MA, agrees, which is why his firm has backed Parthenon Therapeutics, a new startup focused on targeting immune exclusion in tumors. When his team saw Li and An's data, “we were astounded by how much of a role the extracellular matrix actually plays in promoting a tumor microenvironment that can either exclude T cells or, in the case of developing an anti-DDR1 antibody, can allow T cells to infiltrate the tumor,” Gandhi says.
Parthenon launched on November 3 with $65 million in initial funding and a plan to advance a DDR1-directed therapeutic into clinical trials. Both Li and An are scientific advisors to the company.
Finding the right disease and patient population, however, could be a challenge. As Rafael Fridman, PhD, of Wayne State University in Detroit, MI, points out, “not all tumors have this rich collagen environment.”
Some research from other tumor models also indicates that targeting collagen assembly could have negative consequences. Earlier this year, for example, Raghu Kalluri, MD, PhD, and his colleagues at The University of Texas MD Anderson Cancer Center in Houston, reported that depleting collagen around pancreatic tumors in mice resulted in more immune suppression, not less (Cancer Cell 2021;39:548-65.E6).
Given the known antitumor and protumor functions of collagen, Li notes, it's possible that altering the higher-order structure of the protein might be a more favorable therapeutic approach than simply eliminating it. More research, however, is needed to clarify the issue. As Kalluri puts it, “the stromal regulation of cancer needs a bit of a revisit.” –Elie Dolgin
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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