Cancer immunotherapy: How is the new target DDR1 different?

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Cancer immunotherapy: How is the new target DDR1 different?

Tumor immunotherapy is another anti-cancer weapon after radiotherapy, chemotherapy and targeted therapy, but its therapeutic effect is often affected by the immunosuppressive effect of the tumor microenvironment (TME).

There are not only a variety of immunosuppressive cells and cytokines in TME, but also a “physical barrier” composed of extracellular matrix (ECM), which seriously affects the infiltration of immune cells to tumors and greatly reduces the killing effect on tumor cells.

Recently, scientists from George Washington University and other institutions challenged the physical barrier outside the tumor. They discovered that a key molecule called Discoid Domain Receptor 1 (DDR1) actually prevents immune cells from approaching the tumor.

scientists from George Washington University and other institutions challenged the physical barrier outside the tumor. They discovered that a key molecule called Discoid Domain Receptor 1 (DDR1) actually prevents immune cells from approaching the tumor.

Inhibiting the expression of DDR1 can reduce the immunosuppressive effect in TME, paving the way for tumor immunotherapy. Related research results were published in the November 3 issue of Nature.

DDR1 is a tyrosine protein kinase receptor discovered in recent years. Many previous studies have found that DDR1 is closely related to the progression of a series of tumors, including breast cancer, the number one cancer killer in women.

Triple-negative breast cancer (TNBC) accounts for about 15% of all breast cancers. It is characterized by high malignancy and aggressiveness. Compared with other types of breast cancer, it lacks effective therapeutic targets. It has always been a medical problem.

The researchers focused on the ECM that affects the infiltration of immune cells into tumors. Previous strategies that directly target ECM have failed to solve the problem of immunosuppression.

In this study, they found that in the process of cancer progression, a key molecule called DDR1 can make the ECM into a highly ordered state, just like wrapping a layer of “barbed wire” around the tumor. In this way, immunity It is difficult for cells to infiltrate tumor cells to play a killing effect.

The researchers knocked out DDR1 in multiple TNBC mouse models, and the results showed that silencing DDR1 can promote the infiltration of T cells in tumors and inhibit tumor growth.

In terms of mechanism, the extracellular domain of DDR1 can enhance the binding of collagen in ECM, make collagen fibers densely arranged, and prevent immune cells from infiltrating tumors.

Based on this new tumor immunosuppressive mechanism, Professor Zhiqiang An, the co-corresponding author of the paper, developed a neutralizing antibody targeting DDR1, which can destroy the arrangement of collagen fibers in ECM, improve immune infiltration and inhibit tumor cell growth.

In general, this study found an immunosuppressive mechanism, proposed a feasible path for reconfiguring tumor ECM to relieve immunosuppression, and revealed that DDR1 can be used as a new target for tumor immunotherapy.