Study reveals how to improve overall immune response against viral cancers

According to the results published in Nature.

Rebecca Obeng, MD, PhD, MPH, assistant professor of pathology in the Division of Gastrointestinal and Hepatobiliary Pathology and member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, was co-author of the study.

T cells, which contain receptors that allow them to recognize and attack foreign substances, differentiate into various cell subtypes, which help shape and control the immune response. One of these subtypes is cytotoxic CD8 T lymphocytes, which directly kill virus-infected and cancerous cells. Adequate activation and function of these cells is also essential for effective immunotherapeutic treatment for cancer patients.

Previous work had shown that compromised CD8 T cell function is caused by the increased expression of the inhibitory protein receptor molecule PD-1 on the cell surface. This leads to what scientists call “T cell depletion,” in which CD8 T cells ultimately lose their function over time.

Usually, this process helps the immune system resolve itself after it is activated. However, in chronic infection and cancer, PD-1 levels are constantly elevated, which can interfere with the proper functioning of CD8 T cells and the immune response.

In the current study, the researchers analyzed PD-1 positive CD8 T cells from patients diagnosed with human papillomavirus (HPV) positive head and neck cancer, which allowed them to examine tumor-associated virus-specific T cells in a tumor. microenvironment, according to Obeng.

HPV-positive squamous cell carcinoma of the head and neck metastatic to the lymph node. Tumor cells (blue) are surrounded by immune cells in the tumor microenvironment.

Using RNA sequencing, the team identified three PD-1 positive CD8 T cell subsets: TCF7 the gene and other genes associated with PD-1 positive CD8 T cells which are essential for T cell survival; the second subset expressed more effector molecules, representing a transient cell population; and the third subset was characterized by a terminally differentiated genetic signature in which they are unable to differentiate into other cell types.

When the researchers treated PD-1 positive CD8 T cells with an HPV peptide and blocked the PD-1 cell pathway, only the first subset of cells that expressed TCF7 proliferated and differentiated into effector CD8 T cells. This subset is called stem cells because they can regenerate and transform into other CD8 T cell subsets, according to Obeng.

The original thought was that when you block the PD-1 pathway, you invigorate CD8 T cells and somehow get their function back. Now we know that you can not only invigorate CD8 T cells, but also stimulate the differentiation of new effector cells from these strain-like CD8 T cells. “

Rebecca Obeng, MD, PhD, MPH

The current results suggest that additional antigen fragments from the HPV E2 and E5 proteins identified by the researchers should be considered as targets for future vaccines. Additionally, the results highlight the importance of the tumor microenvironment and how therapeutic inventions can alter a tumor microenvironment and impact the overall immune response, Obeng said.