New discovery could lead to better cancer treatment

A type of T cell known as CD4-positive T helper cells has been identified by researchers. These T cells have contributed to the development of a series of antitumor immune mechanisms that allow killer cells to infiltrate deeper into melanomas and breast cancer tumors.

The discovery could improve cancer immunotherapy, a promising therapy that targets cancer cells using the body’s immune system rather than radiation.

Previously considered a simple helper of the immune system, a kind of white blood cell now seems to be the initiator of the body’s defenses against cancerous tumours. The discovery could improve cancer immunotherapy, a promising treatment that targets cancer cells using the body’s immune system rather than radiation.

Washington State University researchers found in an animal study that a population of T cells called CD4-positive T helper cells help initiate a chain of anti-tumor immune defenses that enhance the ability of killer cells to infiltrate melanoma and breast cancer tumors. T cells are a subset of white blood cells called lymphocytes, which circulate throughout the body via the lymphatic system.

The involvement of a specific subset of killer cells known as CD8-positive T cells has been the subject of several previous studies as well as contemporary immunotherapies. However, less than 20% of patients respond to such treatments, and Hui Zhang, the study’s lead author, suggested that the initiating role of CD4-positive helper cells could improve such treatments. The results were recently published in the Journal of Immunology.

“One of the most challenging aspects of current cancer immunotherapy is the low response rate,” said Zhang, assistant professor of pharmaceutical sciences at WSU. “The lack of knowledge on how to improve lymphocyte infiltration into the tumor hampers the success of improving the rate of response to cancer immunotherapy. Our finding holds promise for addressing this issue.

Cancer is the second leading cause of death nationally and globally. Currently, surgery, chemotherapy and radiation therapy are the conventional approaches to treating cancer. However, these approaches cannot cure many cancers because some become metastatic, spreading from the primary tumor throughout the body, and some cancer stem cells can become resistant to chemotherapy and radiation therapy.

A relatively new treatment, immunotherapy has shown promise in curing a range of cancers, but only a relatively small number of patients respond to it. Zhang’s research team hopes to change that through knowledge of the mechanisms that help kick-start the body’s immune defenses.

The immune system has two types of killer cells: CD8 positive T cells and so-called “natural killer” cells. Both can attack virus-infected cells and cancer cells.

Natural killer cells are innate and roam the body. They act as our immune system’s first line of defense but cannot recognize specific antigens on their own – toxins or other foreign substances in the body. After natural killer cells start functioning, CD8 positive T cells, which can recognize specific antigens, arrive. While CD8 positive T cells and their mechanisms have been well studied and are used in current immunotherapies, not much is known about how to activate the antitumor function of natural killer cells.

Using genetic experiments in knockout mice, Zhang’s group found evidence that a certain type of CD4-positive T cells, called tissue-resident memory T cells, may be essential for the activation of these front lines of natural killer cell advocates. Their experiments showed that they were effective against melanoma and breast cancer tumors.

“We found that this specific population of CD4 T cells was the key player in initiating antitumor immunity,” Zhang said.

Specific CD4 T cells, together with natural killer cells, not only killed tumor cells and controlled tumor progression, but also enhanced the infiltration of other white blood cells, or lymphocytes, into the tumor.

In future studies, the researchers plan to continue to investigate the precise cellular and molecular mechanisms of this antitumor immunity, first in mice to develop effective immunotherapy against cancer. Next, the team hopes to move on to clinical trials on human subjects.

“Our goal is to develop a powerful cancer immunotherapy approach that is effective for all patients with different types of cancer,” Zhang said.

Reference: “Tissue-resident memory CD4+ T cells play a dominant role in the initiation of antitumor immunity” by Hui Zhang, Zhaohui Zhu, Samantha Modrak, and Alex Little, June 15, 2022, The Journal of Immunology.
DOI: 10.4049/jimmunol.2100852

This study was funded by the National Institutes of Health as well as start-up funds from the WSU College of Pharmacy and Pharmaceutical Sciences.

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