Researcher: 'We’re hoping to identify a way to counteract that suppressive response, so that we can reactivate the lung-tumor-targeting T cells.'

New research at the Massachusetts Institute of Technology (MIT) has discovered that bacteria present in the lungs create an environment that suppresses the activation of cancer-killing T cells in the nearby lymph nodes, making immunotherapy treatments less effective than elsewhere in the body, according to a press release.

“There is a functional difference between the T-cell responses that are mounted in the different lymph nodes," Stephani Spranger, of MIT’s Koch Institute for Integrative Cancer Research and senior author of the study, said in the release.  "We’re hoping to identify a way to counteract that suppressive response, so that we can reactivate the lung-tumor-targeting T cells."  

The research, done with mice and published in the journal Immunity, focused on understanding why the immune system failed to mount a robust response to lung cancer, even after treatment with immunotherapy drugs, according to the release.

Unlike lymph nodes near tumors growing on the skin, the researchers found an immune-suppressive environment in the lymph nodes near lung tumors, the release stated. This discovery could pave the way for the development of novel strategies to enhance the immune response to lung tumors. The study builds on previous knowledge that cancer cells can emit signals that suppress the immune system, leading to T-cell exhaustion. Immunotherapy aims to recharge these exhausted T cells to allow the cells to target tumors again. 

Spranger's earlier work provided a potential explanation for this discrepancy. In a 2021 paper, she pointed out different dysfunctional T cells that display a distinct gene expression pattern that prevented them from attacking cancer cells within the tumor. Building on this finding, the team explored the underlying causes of this activation failure within the lymph nodes, which are responsible for filtering fluids draining from nearby tissues, the release noted. What's known as "killer T cells" encounter dendritic cells in the lymph nodes, which present antigens that activate T cells. They discovered that T cells in the lymph nodes draining from lung tumors encountered dendritic cells and recognized tumor antigens but failed to become fully activated due to inhibition by another population of T cells called regulatory T cells. The study further revealed that high levels of interferon gamma in the lymph nodes draining from the lungs trigger the activation of regulatory T cells. This signaling molecule is created as a reaction to the presence of commensal bacteria, which naturally occur in the lungs.

Although the specific bacteria inducing this response and the cells producing interferon gamma have yet to be identified, the researchers demonstrated that blocking interferon gamma with an antibody restored the activity of killer T cells, according to the release. However, using that strategy to stimulate killer T cells in patients may not be viable because blocking interferon gamma can dampen the overall immune response against a tumor. Spranger's lab is looking into other ways to trigger the killer T cell response, the release said.