Experiments on mice and human cells reveal that the number of specialised immune cells ready to combat skin cancer increased when a novel therapy prevented their egress from melanoma tumours.
Researchers at NYU Langone Health and its Perlmutter Cancer Center, who conducted the study, discovered that combining immunotherapy with a pharmacological inhibitor of immune cell egress prevented the growth of melanoma tumours in more than half of the examined mice. Before, immunotherapy has been unable to stop the tumours from spreading on their own.
Recent advances in immunotherapies, medications designed to help the body’s immune defence system detect and kill cancer cells, much like it would an invading virus, have greatly improved cancer care, researchers say. The treatments work by boosting the action of immune cells that both directly attack cancer and prevent cancer cells from evading recognition by the immune system.
The latest generation of immunotherapies, called immune checkpoint inhibitors, protect antitumor T cells from inactivation and have become a mainstay in the treatment of melanoma. While these drug treatments do not work for all patients, previous research shows that having more overall T cells, particularly when positioned in the centre of tumours, makes the drugs more effective.
The new study, published in the journal Nature Immunology online on Feb. 27, showed that key immune cells called CD8 T cells escape melanoma tumours when they gather near the tumour periphery as well as nearby lymphatic vessels, which carry immune cells throughout the body. Indeed, the researchers found that more T cells accumulate inside tumours in mice bred to lack lymphatic vessels in their skin.
Further experiments showed that signalling molecules, chemokine CXCL12 and its related receptor protein CXCR4, attract and move T cells toward lymphatic vessels. When researchers blocked either CXCL12 or CXCR4, T cells could not emigrate from the tumour and instead stayed in its centre.
Taken together, the researchers say the results demonstrate how T cells are likely drawn to the tumour’s outer rim by CXCL12 and closer to the lymphatic vessels, where CXCR4 “encourages” the T cells to exit the tumour. When researchers combined immunotherapy with a chemical blocker of CXCR4, the number of T cells in mice tumours doubled and half of the tumours stopped growing.
“Our study confirms for the first time how CD8 T cells are escaping melanoma tumours through chemokine signalling to their nearby lymphatic vessels, leaving tumours less susceptible to anticancer immunotherapy,” said study lead investigator Maria Steele, PhD, a postdoctoral research fellow in the Ronald O. Perelman Department of Dermatology at NYU Grossman School of Medicine and Perlmutter Cancer Center. “These findings reveal that T cells circulate out of tumours, reshaping scientific views of tumour immunology where T cells randomly find and target tumour cells.”
“Our study shows that blocking this escape route lets immunotherapy work better in fighting the growth of skin cancer cells,” said study senior investigator Amanda Lund, PhD.
Among the study’s other results was that T cell leakage depended on their potency, or how strongly they could bind to target proteins on tumour cells. The longer the most potent T cells spent inside tumours, the more likely they were to encounter their target cancer cells and the more likely these T cells were to remain inside the tumour. Increasing the initial time these T cells spend inside the tumour, the researchers say, may help improve therapy.
“These results suggest that it is not only about getting T cells into the melanoma tumour but also about getting these T cells to the right place with the right signals to drive the most specific and durable immune responses,” said Lund, an associate professor in the Ronald O. Perelman Department of Dermatology and in the Department of Pathology at NYU Grossman School of Medicine and Perlmutter Cancer Center. (ANI)