Targeting the secretory pathway in cytotoxic T lymphocytes to modulate their cytolytic capacity in cancer immunotherapy
Final Report Abstract
From our data we infer that the strong response of EBAG9-KO recipient mice in a real organ transplantation model reflects the efficacy of EBAG9-/- CTLs to be activated and to exert a superior effector capacity. This gain of cytotoxic efficacy could be demonstrated in models where mice were challenged with weak alloantigens or minor histocompatibility antigens. Translationally, such strong alloreactivity is in line with the notion that a sufficient graft-versus-leukemia effect in human donor-lymphocyte infusions strongly depends on an alloreactive response. Thus, we consider the modulation of EBAG9 expression in adoptively transferred T cells as a promising strategy to enhance the cytolytic efficacy. From the heart allotransplantation experiments we can also conclude that EBAG9 contributes essentially to the maintenance of graft tolerance. The research plan deviates in some aspects from the working program as detailed in the proposal, in particular induced up-/downregulation of EBAG9 by estrogen or estrogen inhibitor was not feasible. Fetal calf sera, commercially available as estrogen-depleted preparations, did not support growth of primary murine T cell cultures. For the first time, we show that the cytolytic strength of a CTL correlates with its capacity to differentiate into a memory T cell, provided that the antigen stimulus is limited and that priming occurrs under non-inflammatory conditions. This observation relates to the putative role of EBAG9 in memory formation following adoptive T cell therapy. Taken together, our results strongly support an immune-tempering effect of EBAG9 and they have prompted us to take advantage of this function by the targeted deletion of the molecule. We postulate that EBAG9-loss confers CD8+ T cells with an enhanced cytolytic efficiency, allowing us to combine EBAG9-targeted deletion with tumor-selective TCRengineering. Because enhanced granzyme release might be preferentially active against hematopoietic tumors, we suggest to focus on adoptive T cell therapies against leukemias. To complement our efforts in targeting the regulated release of granzymes, we dissected the role of the sorting receptor Sortilin which controls tightly the release of IFN-along the constitutive secretory pathway. We propose that the modulation of Sortilin expression affects the capacity of adoptively transferred T cells to target solid tumors, because a higher peak release of IFN-might lead to an effective destruction of the tumor stroma.
Publications
- 2012. Immunity 37: 854-866
Herda S., Raczkowski F., Mittrücker H.-W., Willimsky G., Gerlach K., Kühl A.A., Breiderhoff T., Willnow TE, Dörken B., Höpken UE, and A. Rehm
