Keeping cancer in check: the potential of checkpoint blockade to treat elderly cancer patients

Globally, the proportion of the population aged 60 and over is growing faster than all younger age groups. While it’s good news that we are living longer, ageing makes us vulnerable to diseases such as cancer. An ageing global population, coupled with declining health, is placing immense pressure on health systems around the world.

Associate Professor Delia Nelson and Dr Connie Jackaman, from the School of Pharmacy and Biomedical Sciences and the Curtin Health Innovation Research Institute at Curtin University, are examining how ageing impairs the immune system’s ability to fight cancer. One aspect of their research involves studying the communication or ‘cross-talk’ changes that occur between ageing immune cells, dendritic cells (DCs) and T cells, and how this cross-talk is affected by inhibitory molecules.

“There is evidence that elderly DCs have a reduced capacity to stimulate T cells, which may contribute to impaired anti-tumour responses in elderly people with cancer,” Nelson says.

“However, little is known about the combined effects of ageing and cancer on DC and T cell inhibitory molecules.”

Nelson, Jackaman and their research team will use their findings to explore the potential for using checkpoint blockade, an immunotherapy that overrides inhibitory molecules, to treat cancer in elderly patients.

“Since most cancer patients are elderly, and the importance of immunotherapy is increasing, studying immune responses to cancer, including DC and T cell interactions, in the older age groups will be crucial to improve the success of cancer immunotherapy,” Jackaman says.

Know your DCs and T cells

The immune system is composed of multiple cell types that recognise and respond to invading foreign material. DCs are important cells in presenting antigens to the immune system. In a young immune system where a tumour is present, DCs stimulate T cells to migrate to the cancer site and directly bind with the target to destroy it. T cells that actively destroy tumour cells are called cytotoxic or ‘killer’ T cells.

“Think of it as a military system: the DCs are the generals, and they direct the T cells to carry out and execute a singular mission, like a tactical response group,” Jackaman says.

“However, T cells are so good at destroying that they need something to stop them, otherwise they will keep attacking, which could lead to the destruction of healthy tissue.”

To ensure immune attenuation occurs after tumour cells have been eliminated, DCs and T cells express immunoinhibitory molecules on their surfaces and release anti-inflammatory cytokines. These small proteins effectively put the brakes on T cells, suppressing their urge to attack.

Inhibitory molecules, also known as checkpoint inhibitory pathways, are vital to maintaining immune homeostasis.

“Inhibitory molecules are newly described regulatory molecules that prevent excessive inflammation and dampen immune responses that could induce autoimmunity,” Nelson says.

Immune cell responses in the elderly

In an ageing immune system, however, the complex chain of immunity events is compromised. Jackaman and Nelson’s research shows that elderly DCs cannot properly stimulate T cells, which impairs their ability to attack cancer cells present in the body, thus enabling the cancer to grow.

They also found that inhibitory DC and T cell expressions increase with ageing. This can result in an increase of negative signals during DC and T cell cross-talk, leading to the promotion of immunoinhibitory molecules, which downregulate T cell responses.

At the same time that the immune system is experiencing this dysfunction, tumour cells also exploit inhibitory molecules, skewing their response to tell T cells to retreat.

“In elderly hosts with cancer, secretion of immunosuppressive factors by tumours may further modulate inhibitory molecules on elderly DCs and T cells. These factors are known to induce DCs and T cells with immune inhibitory functions in young hosts,” Jackaman says.

Releasing the brakes on the immune system

Checkpoint blockade is a novel immunotherapy that directly targets inhibitory molecules and has shown great promise as a cancer treatment.

With checkpoint blockade, the body is injected with antibodies that override inhibitory molecules seized by tumour cells. These proteins release the brakes on T cells, making them free to keep attacking the cancer.

Harnessing the body’s own immune system to fight cancer cells dates back to the late 19th century, but recent advances in antibody medicines have revolutionised immunotherapy as an oncology practice. Checkpoint inhibitor drugs have been used to successfully treat patients with advanced melanoma as well as lung, kidney, colon and bladder cancers.

However, there is still much to learn about the immune system, and while checkpoint inhibitor drugs help some cancer patients, they fail to work for others. In many cases, immunotherapy must be used in conjunction with other treatments, such as radiotherapy and chemotherapy.

Exploring other checkpoint pathways

Jackaman and Nelson’s research has shown that checkpoint blockade can be effective, but it may not be enough to alleviate immunosuppression.

“Our data suggest that checkpoint blockade is indeed likely to help restore immune function in elderly cancer patients. However, given that elderly DC and T cells co-express multiple checkpoint molecules, patients may need to be given more than one checkpoint inhibitor,” Nelson says.

In addition to their research on ageing DCs and T cells, Jackaman and Nelson are examining other immune cells that express inhibitory molecules, such as macrophages, to find additional inhibitory pathways that could potentially be targeted in elderly patients.

Going forward, the researchers will study the underlying mechanisms that alter the functions of ageing key immune cells and inhibitory molecules, which will provide a more detailed understanding of the specific effects of ageing on the immune system. This insight could then inform how inhibitory pathways can best be targeted in elderly cancer patients.

Jackaman and Nelson’s latest research into DCs, T cells and checkpoint inhibitory molecules was supported by the Cancer Council of Western Australia and reviewed in the journal, Ageing Research Reviews.