Bacteria May Cause Anti-Immunotherapy Activity in Patients With Lung Cancer

Current immunotherapies may be less effective for patients with lung cancer because bacteria in their lungs create an environment that suppresses T lymphocyte (T-cell) activation, according to a new study published in Immunity. Dysfunctional T cells are unable to attack cancer cells and decrease immune response, according to the investigators.

“There is a functional difference between the T-cell responses that are mounted in the different lymph nodes. We’re hoping to identify a way to counteract that suppressive response, so that we can reactivate the lung-tumor-targeting T cells,” said senior author Stefani Spranger, Howard S. and Linda B. Stern Career Development assistant professor of Biology and a member of MIT’s Koch Institute for Integrative Cancer Research, in a press release.

Immune checkpoint inhibitors (ICIs) are a common immunotherapy that enables the immune system to attack tumors. ICIs reactivate exhausted T cells (caused by cancer cells that send immunosuppressive signals) and are often effective against cancers such as melanoma. Unfortunately, lung cancer does not respond well to ICIs.

Throughout her research, Spranger observed that dysfunctional T cells can be distinguished from normal T cells. The dysfunctional cells had a different pattern of gene expression and, upon entering a tumor, were unable to attack cancer cells.

To understand why some T cells were not being properly activated, Spranger and colleagues studied mice implanted with genetically identical tumors in their lungs or the flank. They observed that the failure of killer T cells to activate occurred in the lymph nodes, when the T cells encountered dendritic cells. When functioning properly, dendritic cells will provide T cells tumor proteins called antigens that facilitate T cell activation and immune response.

However, in patients with lung cancer, the investigative team discovered that the dendritic cells are being suppressed by regulatory T cells, which normally prevent the immune system from attacking the body’s own cells. In this instance, the regulatory cells removed the dendritic cells’ stimulatory proteins, which consequentially disabled and prevented the dendritic cell from activating the killer T cells.

Investigators also found that interferon gamma—a signaling molecule that is typically activated by non-infection causing lung bacteria—was being activated by regulatory T cells in the lymph nodes. The researchers do not wholly understand why the bacteria are creating this response, nor do they have knowledge about the cells producing the interferon gamma.

What they observed is that killer T cell activity could be reactivated in the mice who were treated with an antibody that blocks interferon gamma. The team will continue to research new ways of stimulating killer T cell responses, which can include methods such as inhibiting regulatory T cells or blocking signals from the bacteria who activate interferon gamma.

Reference

Massachusetts Institute of Technology. Why lung cancer doesn’t respond well to immunotherapy. News Release. February 2, 2023. Accessed on February 3, 2023.