A new study suggests that some T Cells become non-responsive to immune checkpoint blockade (ICB) early in the course of Non-small Cell Lung Cancer (NSCLC), the most common form of this disease. The report also suggests a possible strategy for improving ICB success.
The study was published last week in Science Immunology. The lead author is Brendan Horton, a postdoctoral fellow at MIT’s Koch Institute for Integrative Cancer Research.
ICB reinvigorates “exhausted” T cells, and has become a standard NSCLC treatment. However, only about 35% of NSCLC patients respond to it. Scientists have long thought that the conditions within a tumor were responsible for determining when T cells stop working. Physicians prescribe ICB to stimulate exhausted T cells.
This new study was done in an orthotopic NSCLC mouse model. It shows that some ICB-resistant T cells stop working before they even enter the tumor. These T cells are not actually exhausted, but rather they become dysfunctional due to changes in gene expression that arise early during the activation of a T cell, which occurs in lymph nodes.
The notion that the dysfunctional state that leads to ICB resistance arises before T cells enter the tumor is quite novel, says Stefani Spranger, a member of the Koch Institute for Integrative Cancer Research, and the study’s senior author.
“We show that this state is actually a preset condition, and that the T cells are already non-responsive to therapy before they enter the tumor,” she says. As a result, she explains, ICB therapies that work by reinvigorating exhausted T cells within the tumor are less likely to be effective. This suggests that combining ICB with other forms of immunotherapy that target T cells differently might be a more effective approach to help the immune system combat NSCLC.
To determine why some tumors are resistant to ICB, Horton and his colleagues sequenced messenger RNA from the responsive and non-responsive T cells in order to identify any differences. They used a technique called Seq-Well, developed in the lab of fellow Koch Institute member J. Christopher Love, a co-author of the study. The technique allows for the rapid gene expression profiling of single cells, which permitted Spranger and Horton to get a very granular look at the gene expression patterns of the T cells under study.
Seq-Well revealed distinct patterns of gene expression between the responsive and non-responsive T cells. These differences, which are determined when the T cells assume their specialized functional states, may be the underlying cause of ICB resistance.
Once Horton and his colleagues had a possible explanation for why some T cells did not respond to ICB, they decided to see if they could help the ICB-resistant T cells kill tumor cells. When analyzing the gene expression patterns of the non-responsive T cells, the researchers had noticed that these T cells had a lower expression of receptors for certain cytokines. To counteract this, the researchers treated lung tumors in murine models with extra cytokines. They found that the previously non-responsive T cells were then able to fight the tumors — meaning that the cytokine therapy prevented, and potentially even reversed, the dysfunctionality.
Cytokine therapy is not currently safe, because cytokines can cause serious side effects including a reaction called a “cytokine storm,” which can produce high fevers, inflammation, fatigue, and nausea. However, there are ongoing efforts to figure out how to safely administer cytokines to specific tumors. In the future, Spranger and Horton suspect that cytokine therapy could be used in combination with ICB.
“This is potentially something that could be translated into a therapeutic that could increase the therapy response rate in non-small cell lung cancer,” Horton says.