An overlooked population of immune cells could offer a new way to attack one of the deadliest forms of lung cancer.
Researchers at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Australia found that specialized immune cells called gamma delta (γδ) T cells can spot and kill small cell lung cancer (SCLC). Their recently published investigation also suggests that existing drugs could strengthen this response, potentially expanding the benefits of immunotherapy.
Roughly 10 to 15% of all lung cancer cases are classified as a small cell carcinoma. Commonly associated with environmental risk factors such as smoking or exposure to hazards like radon, the rare but aggressively fast-growing condition gets its name from the unusually tiny appearance of its cells.
Non-small cell lung carcinomas, such as the adenocarcinoma Pope Leo XIV was diagnosed with, tend to respond well to surgery, chemotherapy, and immunotherapy when spotted early. Although chemotherapy combined with immunotherapy is now standard treatment for advanced SCLC, long-lasting responses remain uncommon. The cancer’s five-year survival rate is less than 7%, according to WEHI.
“For decades, we’ve known that small cell lung cancer is exceptionally good at hiding from the immune system,” says senior author and laboratory head Kate Sutherland. “We’ve found an immune cell that appears to be able to see through that disguise.”
One reason is that these tumors can edit their genes to suppress the production of major histocompatibility complex class I (MHC-I) molecules, which allow conventional T cells to recognize the cancers through protein fragments on the tumor cells’ surfaces.
Gamma delta T cells are different. Unlike conventional T cells, this small subset of peripheral immune cells can detect cellular stress, potentially allowing them to detect cancers that have otherwise become difficult to identify.
To profile their activity in patients with SCLC, the researchers analyzed tumor samples and non-affected biopsies from a dozen patients using single-cell RNA sequencing and immunophenotyping. They found gamma delta T cells in every patient’s samples, with evidence that the cells had what it takes to attack the cancerous cells.
An analysis of data from two previous clinical trials also showed that patients whose tumors showed stronger gamma delta T cell signatures tended to have better overall survival when treated with immune checkpoint inhibitors during chemotherapy.
With these insights in mind, the team generated miniature models of the cancer in the lab using donated SCLC cells to test the effects of existing therapies that could encourage gamma delta T cells to kill the tumors.
One approach involved tarlatamab, a drug that links a tumor-associated protein called DLL3 with the CD3 receptor on T cells, bringing them into closer contact. In cell cultures, the researchers found that gamma delta T cells could kill the cancer cells when redirected by the drug.
A second approach involved zoledronate, a drug already used to treat osteoporosis and complications of cancer affecting the bones. The medication changed pathways inside the cancer cells, making them more susceptible to attack by a subset of gamma delta T cells.
The findings raise the possibility of developing treatments that expand a patient’s gamma delta T cells outside the body before returning them to fight the cancer. Such approaches, known as adoptive cell therapies, are already being investigated for other cancers.
Zoledronate might also offer a way to increase the number and activity of these immune cells, while tarlatamab could help direct their attack towards tumors.
Larger studies involving more donated samples and animal models will be needed to establish which patients might benefit and whether the approach improves survival.
For now, the study identifies a previously underappreciated part of the immune system that could help overcome one of SCLC’s most persistent defenses.
Rather than relying solely on conventional T cells, future treatments may be able to exploit gamma delta T cells to expose a vulnerability in a cancer that has proved exceptionally difficult to treat.
This research was published in Cancer Cell
Source: WEHI
