Scientists Discover Molecule That Prevents Immune System From Attacking Cancer Cells

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Australian scientists have discovered the structure of a molecule that restrains the immune system’s ability to target cancer cells.

The structure, known as the LAG-3/HLA-II complex, was discovered by Monash University researchers and is the first study to show its crystal structure.

Known as an “immune checkpoint molecule,” the function of the LAG-3/HLA-II complex is to inhibit the immune system’s response—an action that cancer immunotherapy aims to restrain.

Immune checkpoint molecules regulate the immune system so that tissue damage is minimised during an immune response.

Despite being identified decades ago, the interaction between the LAG-3 receptor and the HLA-II ligand has been “uncertain”—especially when other immune checkpoint molecules, such as PD-1 and CTLA-4, have been better studied—the study’s lead author Dr. Jan Petersen said.

Petersen said the discovery will allow researchers to develop drugs that can be used to modulate and block LAG-3 activity—thus improving the effectiveness of cancer immunotherapy.

Immunotherapy and Cancer Treatment

Immunotherapy works by boosting the body’s own system to target different types of cancers, or by removing barriers to the immune system attacking the cancer, according to Cancer Council Australia.

There are various types of immunotherapy, such as immune stimulants, Chimeric antigen receptor (CAR) T-cell therapy, oncolytic virus therapy, cancer treatment vaccines, and immune checkpoint inhibitors.

How the Immune System and Its Inhibitors Function

When bacteria and viruses enter the body, the body’s white blood cells or lymphocytes respond by fighting the foreign body.

B cells fight bacteria and viruses, while T cells control the immune system and assist B cells make antibodies.

T cells also bind and recognise partner proteins on immune checkpoints (common ones include PD-1, CTLA-4, and LAG-3), to protect the body from being attacked by its immune system.

Cancer cells belong to the host, meaning they are not targeted by the immune system.

Immune checkpoint inhibitors aim to alter this process by blocking proteins or “checkpoints” on the T cell that stop the immune system from attacking cancer cells. Instead, the use of immune inhibitors allows T cells recognise and destroy cancer cells.

PD-1 and CTLA-4 are well studied, with many studies and therapies showing they can modulate T cell responses. On the other hand, LAG-3 is less understood. The mechanisms for LAG-3 binding to HLA-II and other cellular components are unclear.

The Monash University study is the first to show the crystal structure of a human LAG-3/HLA-II complex, according to the press release. This outcome sets the foundation for future developments into drugs that target LAG-3, opening a new avenue into cancer immunotherapy.

Checkpoint Inhibitor Drugs in Australia

In Australia, checkpoint inhibitor drugs are currently the most widely used form of immunotherapy, and are used for some types of cancers including including bladder, head and neck, Hodgkin and non-Hodgkin lymphoma, kidney, liver, lung, melanoma, and Merkel cell carcinoma. These drugs are usually given intravenously.

Common side effects include fatigue, skin rash and itching, diarrhoea, abdominal pain, dry eyes, changes in weight and body temperature, and joint pain, according to Cancer Council Australia.

However, Cancer Council Victoria states that while checkpoint inhibitors have worked well for some people, “it does not help everyone.”

“Sometimes more than one type of immunotherapy drug is prescribed,” the Cancer Council Australia website states.

“Immunotherapy drugs appear to keep working for varying periods of time, and in some cases, can keep working long after other treatments are no longer used.”