Immunotherapy, now in widespread use as a treatment for cancer, continues to be a focus of research and to teach us more about the immune system. A new study by scientists at the Institut Pasteur has identified a novel mechanism of action of anti-PD-1 antibodies, a commonly used form of immunotherapy.
Since the 2010s, immunotherapy has rapidly gained ground as a form of treatment for cancer. There are now several different types of immunotherapy, each aimed at harnessing the patient's immune system so that it tackles cancer cells by itself. These innovative therapies were recognized with the 2018 Nobel Prize in Medicine.
Anti-PD-1 antibodies are a type of immunotherapy used to treat various forms of cancer including lung, kidney and skin cancer. They represent an effective treatment that can be long lasting in some patients. Their mechanism of action was thought to be well known: in the tumor, white blood cells known as T cells begin expressing the PD1 receptor, which, when it interacts with cancer cells, transmits a negative signal that prevents the T cells from destroying tumors. "By blocking this receptor, anti-PD-1 antibodies stimulate killer cells in the immune system," explains Philippe Bousso, Head of the Dynamics of Immune Responses Unit at the Institut Pasteur.
A specific mechanism of action in the lymph nodes
The mechanism of anti-PD-1 antibodies in the tumor itself is therefore well established. But what Philippe Bousso's team discovered was that this was not the only place in the body where they were acting. Since the antibodies were injected into the bloodstream, they could be found all over the body – including in the lymph nodes, organs where many immune responses are initiated. "The first finding we made was that in the lymph nodes the antibodies recruit new lymphocytes to fight the tumor," explains Marion Guérin, a scientist in Philippe Bousso's unit. "The second thing we found was that the antibodies have a very different mechanism of action in the lymph nodes from that observed in the tumor."
While in the tumor the antibodies bind to killer cells known as CD8+ T cells, in the lymph nodes they interact much more with T follicular helper cells, a type of CD4+ T cells. T follicular helper cells do not attack the tumor directly; instead they secrete the molecule interleukin 4, which stimulates the proliferation of killer cells.
It is shown that follicular helper T cells are the primary cells targeted by anti-PD-1 Ab in tumor-draining lymph nodes.
Copyright: Institut Pasteur - Margot Bardou- Mathilde Ruggiu- Marion Guérin – Philippe Bousso
Highlighting the key role of lymph nodes in immunotherapy
"This whole chain of reactions has a significant impact on the anti-tumor response," emphasizes Marion Guérin. "The recruited cells migrate from the lymph nodes to the tumor to amplify the immune response that has already begun there." The scientists' findings therefore reveal a key mechanism in the efficacy of immunotherapy based on anti-PD-1 antibodies. The results highlight the role of the lymph nodes in the immune response against the tumor, which should be taken into account when monitoring patient treatment. For example, in patients who need surgery to remove lymph nodes, it is important to determine whether giving them antibodies before or after the operation will be most beneficial.
The study also points to CD4+ T cells and the interleukin 4 that they produce as parameters that should be considered in immunotherapy treatment to maximize its effectiveness. T follicular helper cells are also an interesting avenue to explore for the development of treatments aimed at patients with an incomplete response to antibodies or experiencing a relapse. "They represent promising targets for developing novel therapeutic approaches," says Philippe Bousso.
Source :
Anti-PD-1 therapy triggers Tfh cell–dependent IL-4 release to boost CD8 T cell responses in tumor-draining lymph nodes, Journal of Experimental Medicine, February 28 2024