Research provides new insight into fundamental workings of the immune system in response to therapy to treat skin cance

New research led by the University of Birmingham suggests that skin cancer patients could have a better prognosis if their T cells send messages from five specific genes in their immune response to drugs given to treat the disease.

The research, carried out in mice, cells in the laboratory, and using publicly available data from patients with advanced melanoma before and after treatment with Nivolumab therapy, is published in Immunity.                         

T cells are white blood cells that protect the body from harm from viruses, bacteria, and cancer cells, and explore their environments by using their T cell receptor (TCR) to recognise fragments, called antigens, of microbes or damaged cancer cells.

The TCR controls the behaviour of the T cell and can send messages to the T cells’ command centre to kick-start an immune response. This process is important for vaccine research and treatment of autoimmune conditions, but is particularly of interest for cancer treatments to improve the anti-tumour function of T cells.

The researchers carried out the study to better understand how the amount of antigen controls how the TCR sends messages to the T cells’ command centre, and how this affects the type of immune response.

They wanted to explore how antigen amounts control the expression of so-called ‘immune checkpoints’ that act as brakes on immune responses. It is these immune brakes, such as one called PD1, that are the target of drugs that seek to increase the immune response in cancer immunotherapy.

Lead author Dr David Bending, of the University of Birmingham’s Institute of Immunology and Immunotherapy, explained:  “Through our research we discovered that the amount of antigen determined how many immune checkpoints or immune brakes a T cell had on its cell surface.”

“When we exposed T cells to the highest amounts of antigen, they stopped sending signals to their command centre, and this was because they had increased the number of immune brakes, which shut down the messengers. This made these T cells unable to respond to antigens for a period.”

By blocking one of the immune brakes, called PD1, the researchers were able to re-awaken some of these ‘unresponsive’ T cells. They found that these re-awakened T cells not only started sending messages to their command centres, but the messages they sent were louder and clearer.

“The response from the command centre was that the T cells started to increase the number of messages from five specific genes,” added Dr Bending.

“By looking for the messages from these five genes, we were able to show that these stronger and louder messages were increased in melanoma patients who survived for longer on drugs that block the immune brake PD1. We think that this means that those cancer patients whose immune cells can send messages from these five genes in response to drugs that target PD1, a good outcome is far more likely.”

The researchers said their finding shows that the immune system likely requires an optimal level of stimulation to mount the most effective immune response in skin cancer patients.

Dr Bending added: “Our research gives us interesting insight into fundamental workings of the immune system. It suggests that both the amount of antigen around a T cell and also the number of immune brakes the T cells have at their surface are very important in controlling immune responses. Furthermore, we have shown that we can alter the balance of the immune response through stopping some of these immune brakes, which results in a stronger T cell response.”

The study has generated a new potential readout to monitor patients on drugs targeting PD1 in cancer. It also may be useful for exploring the potential of combinations of drugs that target multiple immune checkpoints to try to further re-awaken T cells in cancer patients.

Overall cancer mortality continues to decline in the US

Cancer death rates continued to decline in men, women, and children in the United States from 1999 to 2016, according to the latest Annual Report to the Nation on the Status of Cancer.

According to the National Institute of Health, overall cancer incidence rates, or rates of new cancers, decreased in men from 2008 to 2015, after increasing from 1999 to 2008, and were stable in women from 1999 to 2015. In a special section of the report, researchers looked at cancer rates and trends in adults ages 20 to 49.

The annual report is a collaborative effort among the National Cancer Institute (NCI), part of the National Institutes of Health; the Centers for Disease Control and Prevention (CDC); the American Cancer Society (ACS); and the North American Association of Central Cancer Registries (NAACCR). The report appeared in the Journal of the National Cancer Institute on May 30, 2019.

“We are encouraged by the fact that this year’s report continues to show declining cancer mortality for men, women, and children, as well as other indicators of progress,” said Betsy A. Kohler, executive director of NAACCR. “There are also several findings that highlight the importance of continued research and cancer prevention efforts.”

The special section shows a different picture for cancer incidence and mortality among men and women ages 20 to 49 than among people of all ages. In the main report, from 2011 to 2015, the average annual incidence rate for all cancer sites combined was about 1.2 times higher among men than among women, and from 2012 to 2016, the average annual death rate among men (all ages) was 1.4 times the rate among women. However, when the researchers looked only at men and women ages 20 to 49, they found that both incidence and death rates were higher among women.

The authors reported that, in the 20–49 age group from 2011 to 2015, the average annual incidence rate for all invasive cancers was 115.3 (per 100,000 people) among men, compared with 203.3 among women, with cancer incidence rates decreasing an average of 0.7% per year among men and increasing an average of 1.3% per year among women. During the period from 2012 to 2016, the average annual cancer death rate was 22.8 (per 100,000 people) among men and 27.1 among women in this age group.

The most common cancers and their incidence rates among women ages 20 to 49 were breast (73.2 per 100,000 people), thyroid (28.4), and melanoma of the skin (14.1), with breast cancer incidence far exceeding the incidence of any other cancer. The most common cancers among men ages 20 to 49 were colon and rectum (13.1), testis (10.7), and melanoma of the skin (9.8).

“The greater cancer burden among women than men ages 20 to 49 was a striking finding of this study,” said Elizabeth Ward, Ph.D., lead author of the study and a consultant at NAACCR. “The high burden of breast cancer relative to other cancers in this age group reinforces the importance of research on prevention, early detection, and treatment of breast cancer in younger women.”

Other notable findings about cancer mortality from the report include that from 2012 to 2016:

• Overall death rates decreased 1.8% per year in men and 1.4% per year in women.
• Among men, death rates decreased for 10 of the 19 most common cancers but increased for 6 cancers, with the steepest increases for liver cancer, oral cavity and pharynx cancer, and non-melanoma skin cancer.
• Among women, death rates decreased for 13 of the 20 most common cancers, including the 3 most common cancers (lung and bronchus, breast, and colorectal), but increased for 5 cancer types, with the steepest increases for cancers of the uterus and liver.

For cancer incidence, from 2011 to 2015:

• Incidence rates for all cancers combined were stable in women and decreased 2.1% per year in men.
• Among men, rates of new cancers decreased for eight of the 17 most common cancers, increased for seven cancers, and were stable for two cancers.
• Among women, rates of new cancers decreased for six of the 18 most common cancers, increased for nine cancers, and were stable for three cancers.