Maria Semitekolou

Speaker for Pulmonology Conferences 2021 - Maria Semitekolou
Maria Semitekolou
Biomedical Research Foundation of the Academy of Athens, Greece
Title : Activin-A protects against lung cancer progression by boosting anti-tumor T cell responses

Abstract:

Activin-A is a pleiotropic cytokine that exerts diverse effects on immune responses depending on the spatiotemporal context; still its precise role in shaping anti-tumor T cell-mediated immune responses remains ill defined.
In order to evaluate whether activin-A directs effective, T cell-mediated anti-tumor responses during lung cancer development, we utilized a syngeneic mouse lung cancer model induced by Lewis Lung Carcinoma cells and administered activin-A therapeutically. In a complementary approach, we disrupted activin-A’s signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A’s type I receptor, ALK4. Using adoptive T cell transfer experiments, we evaluated whether ex vivo administration of activin-A on CD4+ T cell obtained from murine lung tumors, protects against lung tumor formation in CD4 KO recipients. Finally, in a preclinical setting, we examine the effects of ex vivo activin-A treatment on the phenotypic characteristics and effector capacity of tumor-infiltrating T cells from lung cancer patients.
Our findings reveal that activin-A administration led to a marked regression in lung cancer progression, evidenced by macroscopic, PET/CT imaging and histological studies, concomitant with a greatly extended overall survival. Activin-A’s anti-tumor effects were associated with increased infiltration of CD4+ T effector cells in lung tumors and decreased frequencies of Foxp3+ Treg and myeloid derived suppressor cells. Moreover, activin-A treatment significantly decreased the expression of several immune checkpoint inhibitors among lung TILs. Mechanistic studies demonstrated that disruption of its signaling on CD4+ T cells, resulted in enhanced tumor progression accompanied by diminished effector responses and heightened percentages of Foxp3+ Treg cells and immune checkpoint inhibitors. Furthermore, CD4+ T cells from CD4/ALK4-KO mice exhibited impaired T cell proliferation capacity compared to CD4+ T cells obtained from healthy mice, indicative of an exhausted phenotype. Therapeutic administration of CD4+ T cell obtained from murine lung tumors and treated ex vivo with activin-A resulted in delayed formation of lung tumors accompanied by enhanced anti-tumor T-cell mediated immune responses.
In our translational studies, ex vivo administration of activin-A on tumor infiltrating leukocytes isolated from human lung cancer specimens resulted in the enhancement of an effector Th cell profile on CD4+ T cells, as evidenced by upregulation of TBX21, GATA3 and RORC. Notably, activin-A-treated CD4+ T cells were less able to suppress the proliferation of autologous naive CD4+ T cells. Additionally, we observed upregulation of TBX21, IRF4, GZMB and PRF1 in CD8+ T cells, upon ex vivo activin-A administration, suggesting that activin-A could be involved in the enhancement of the effector functions of tumor infiltrating CD8+ T cells.
To conclude, our studies reveal a novel role for activin-A in enhancing anti-tumor T cell-mediated responses that may be beneficial in the combat against lung cancer.

Biography:

I am currently a Post-Doctoral Researcher at the Cellular Immunology Laboratory in Biomedical Research Foundation of the Academy of Athens in Greece and my research interests are focused on investigating the role of immunomodulatory cytokines and regulatory T cells in the control of T cell-driven immune responses. I have been actively involved in several projects that are published in high impact factor journals (JEM, Nat Med, JACI, ERS, PNAS). Lately, I begun expanding my scientific interests in delineating the role of the cytokine, activin-A in guiding anti-tumor immune responses in mouse models of lung cancer as well as in preclinical settings, using primary lung tumors from human patients.

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