Arginase-1-based vaccination against the tumor microenvironment: the identification of an optimal T-cell epitope
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l-arginine depletion by regulatory cells and cancer cells expressing arginase-1 (Arg-1) is a vital contributor to the immunosuppressive tumor microenvironment in patients with cancer. We have recently described the existence of pro-inflammatory effector T cells that recognize Arg-1. Hence, Arg-1-specific self-reactive T cells are a naturally occurring part of the memory T-cell repertoire of the human immune system. Here, we further characterize a highly immunogenic epitope from Arg-1. We describe frequent T-cell-based immune responses against this epitope in patients with cancer, as well as in healthy donors. Furthermore, we show that Arg-1-specific T cells expand in response to the TH2 cytokine interleukin (IL)-4 without any specific stimulation. Arg-1-specific memory TH1 cells that respond to increased IL-4 concentration may, therefore, drive the immune response back into the TH1 pathway. Arg-1-specific T cells thus appear to have an important function in immune regulation. Because Arg-1 plays an important role in the immunosuppressive microenvironment in most cancers, an immune modulatory vaccination approach can readily be employed to tilt the balance away from immune suppression in these settings.
KeywordsArginase Anti-regulatory T cells Immune-modulating vaccines IO112 PIVAC 18
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MHA designed and supervised the study. EM designed the experiments and analyzed the data. EM, SMA, SKB, MAJ, and SEWB performed experiments. IMS provided the relevant clinical material. All authors contributed to drafting the manuscript.
This work has been supported by grants from the Danish Cancer Society (Grant number R146-A9440-16-S2), Herlev Hospital (CCIT-Dk funding) and Innovation Fund Denmark (Grant number 8054-00058B).
Compliance with the ethical standards
Conflict of interest
Mads Hald Andersen has filed several patent applications based on the use of arginase for vaccinations. The rights of the patent applications have been transferred to Copenhagen University Hospital, Herlev, in accordance with the Danish Law of Public Inventions at Public Research Institutions. The capital region has licensed these patents to the company IO Biotech ApS, whose purpose is to develop immune-modulating vaccines for cancer treatments. Mads Hald Andersen is a shareholder and board member of IO Biotech ApS. Evelina Martinenaite is employed by IO Biotech ApS. Other authors declare no conflict of interest.
Ethical approval and ethical standards
The protocol was approved by the Scientific Ethics Committee for the Capital Region of Denmark (H-A-2009-013) and conducted in accordance with the provisions of the Declaration of Helsinki.
Written informed consent for the use of the PBMCs for research purposes was obtained from the patients and healthy donors prior to inclusion in the study.
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