Research / Alissafi Lab

RESEARCH FOCUS

The research interests of our group are focused on delineating the molecular and cellular mechanisms governing the function of immune regulatory networks that restrain aberrant immune responses in cancer and autoimmunity and block the effect of immunotherapy (Grigoriou et al Cancer Immunology Research 2021, Alissafi et al Cell Metabolism 2020, Alissafi et al JCI 2018, Alissafi et al JCI 2017), with ultimate goal the translation of these basic immunological mechanisms into targeted therapies and development of biomarkers. Our research has been recently funded by the European Research Council (RegSign ERC STG2020) and the Hellenic Foundation for Research and Innovation (AUTOREG 2nd PostDoc Grant).

Immune Regulation

CANCER

AutoImmunity

Metabolism

Regulatory T Cells

Dendritic Cells

Exploring the function of immune regulatory networks in autoimmune diseases

Autoimmune diseases comprise a heterogenous group of inflammatory responses against self tissues or cells, that develop upon failure of immune regulatory cells (such as Regulatory T cells and Dendritic Cells) to restrain autoimmune inflammation. Previous studies from our group have unraveled novel mechanisms of function of these regulatory cells during the course of autoimmune diseases (Alissafi et al JCI 2017, Alissafi et al JI 2015, Ioannou et al. JI 2013) and have for the first time highlighted that their metabolic dysfunction can be in part responsible for the development of autoimmunity (Alissafi et al, Cell Metabolism 2020). However, the molecular mechanisms and the triggers that determine the deterioration of regulatory cells in autoimmune diseases remain ill defined. An in depth understanding of the mechanisms that drive the metabolic rewiring of regulatory cells would ease the design of immunotherapies in numeral clinical settings such as autoimmunity, cancer and transplantation in which disturbed tolerance is a common denominator.

Armed with a thorough knowledge on immunoregulation and its translational implications, through our collaboration with expert clinicians in the field, our ongoing and future studies aim to exploit why regulatory networks are not able to modulate immune system attack on the body and prevent autoimmune responses. The vast majority of autoimmune diseases develop as a consequence of complex mechanisms that depend on genetic, epigenetic, molecular, cellular, and environmental elements and result in defects in immune regulatory checkpoints of tolerance, such as DCs and Tregs, and ultimately in the breakdown of immune tolerance. Focusing on the interplay of DCs and Tregs, we wish to delineate which mechanisms of their function are defective during autoimmune diseases in order to develop targeted therapeutic strategies with the goal of restoring immune tolerance.

Targeting immune regulatory networks in cancer

Fundamental discoveries made over the last decade have unequivocally shown that the immune system plays a vital role in tumor development with tumors exploiting sophisticated immune tolerance networks to avoid immune recognition and destruction. Specifically, regulatory T cells (Tregs) myeloid-derived suppressor cells (MDSCs) and regulatory dendritic cells (DCs) accumulate into tumors and form a highly immunosuppressive tumor microenvironment (Alissafi T. et al J Autoimmunity 2019, Hatziioannou, A., Alissafi, T., Verginis, P. 2017 J Leukoc Biol). Suppression mechanisms employed by these networks contribute significantly to the failure of current therapeutic strategies that rely on induction and potentiation of anti-tumor immune responses (Alissafi T. et al. Journal of Clinical Investigation 2018).

Despite major advances in our understanding of tumor tolerance mechanisms and the emerging success of immunotherapy, cancer remains one of the leading causes of death globally. Cancer immunotherapy using immune checkpoint inhibitors (ICIs), promises durable and sustained responses only in small proportion of cancer patients and most importantly responses are often accompanied by severe adverse effects such as life-threatening autoimmune manifestations termed immune-related adverse events (irAEs). Deciphering new strategies to harness the anti-tumor immunity while keeping in check the autoimmune responses remains a daunting task and could ultimately lead to more effective management of cancer. Currently used ICI can also target Tregs, thus it is plausible that development of autoimmune side effects can be attributed to Treg de-stabilization or aberrant plasticity (Grigoriou M Cancer Immunology Research 2021, Alissafi T et al Cell metabolism 2020, Alissafi et al JCI 2017). Building on these findings our future research wishes to apply lessons learned from regulatory networks in autoimmunity to manage adverse toxicities in cancer patients treated with immunotherapy.