Expansion of Tumor-Associated Treg Cells upon Disruption of a CTLA-4-Dependent Feedback Loop
This week we profile a recent publication in Cell from Dr. Thorsten Mempel’s (pictured, right) lab
at Massachusetts General Hospital and Harvard Medical School with first author Dr. Francesco Marangoni (left).
Can you provide a brief overview of your lab’s current research focus?
Our lab’s general interest is to understand how the communication between cells of the innate and the adaptive arms of the immune system is organized in our body’s tissues. Concretely, we primarily study how the interactions of antigen-presenting dendritic cells (DCs) and various types of T cells are orchestrated both in secondary lymphoid organs where adaptive immune responses are initiated as well as at sites of inflammation. This includes the question of how these cells traffic between tissues via the blood and lymph streams and how they dynamically position themselves within tissues in order to interact in useful ways. We also try to understand what kind of information exchange occurs during these interactions beyond the activation signals that T cells receive from DCs. The T cell types we are most interested in are cytotoxic T lymphocytes and regulatory T cells, and we study these cells mostly in mouse models of cancer, where they both play pivotal roles in the outcome of both spontaneous as we as therapeutically induced anti-tumor immune responses. This has the benefit that our findings have the potential to be translated very directly into new cancer immunotherapy strategies.
What is the significance of the findings in this publication?
T regulatory (Treg) cells generally restrain the ability of our immune system to control or eliminate malignant tumors. In this study we found that one of the activities of Treg cells in the tumor microenvironment is to deplete the co-stimulatory molecules CD80 and CD86 from the surface of dendritic cells they interact with, using a molecule called CTLA-4. This is predicted to reduce the ability of these DCs to activate anti-tumor effector T cells. Surprisingly, we observed that when we blocked CTLA-4 using antibodies, Treg cells started to proliferate vigorously and increased in numbers even more than effector T cells did, both in tumors and in tumor-draining lymph nodes. It turned out that Treg cells, by reducing co-stimulation on DCs in their local tissue environment, also regulate their own activation for which they depend on signals through CD28, the receptor for CD80 and CD86. Preventing Treg cells from reducing CD80 and CD86 on DC therefore caused their “hyper-activation”. This raised the question of whether the expanding Treg cells still suppress antitumor immunity even when deprived of their ability to use CTLA-4 to reduce co-stimulatory molecules on DCs. We found that inactivating Treg cells while blocking CTLA-4 indeed enhanced the anti-tumor effect of CTLA-4 blocking antibodies, which indicates that Treg cells continue to deploy additional mechanisms of suppression. Our findings are significant because they revealed a new way by which Treg cells “self-regulate”. We speculate that this form of feedback control could physiologically serve to prevent Treg cells from “over-regulating” useful immune responses against pathogens, which would otherwise allow the pathogens to escape control by the immune system. Our findings also suggest that Treg cell hyper-proliferation in response to CTLA-4-blocking immune checkpoint therapy may partially off-set the therapeutic efficacy of this form of
What are the next steps for this research?
Our results indicate that strategies to deplete or inactivate Treg cells specifically in tumors may synergize with CTLA-4-targeted immune checkpoint therapy in cancer patients. We therefore continue to explore unique attributes of tumor-infiltrating Treg cells in mouse models of cancer that could be the basis for their selective therapeutic targeting in humans.
This research was funded by:
NIH grants AI R01 AI123349, R21 AR072849, and an Established Investigator Award by the Melanoma Research Foundation.