Marinos Kallikourdis read Natural Sciences at Trinity College, Cambridge (UK) under the supervision of M.S. Neuberger, where he also received a PhD in Immunology for work done in the MRC Laboratory of Molecular Biology (Cambridge, UK), home of the discovery of DNA structure and the invention of monoclonal and humanized antibodies. He was part of the team, led by A.G. Betz, that first demonstrated the requirement for regulatory T cells in the sustenance of maternal-fetal tolerance and deciphered the mechanism of pregnancy-associated amelioration of Rheumatoid Arthritis. After a short post-doc with A. Viola, he became a Principal Investigator in Humanitas and Assistant Professor of General Pathology and Immunology in the Department of Medical Biotechnology and Translational Medicine, University of Milan. In 2015 he became Assistant Professor of General Pathology and Immunology at Humanitas University. His research group now focuses on cardio-immunology (See next sections).
Teaching I formally commenced teaching as a college supervisor for Biochemistry at Trinity College, Cambridge, whilst studying for my PhD. In the collegiate supervision system, emphasis is given at stimulating the students’ ability to use their reasoning in order to ask and decipher complex scientific questions; this centuries-old principle remains a key guideline to how I approach lecturing. As a faculty member of the University of Milan (2012-2015), I taught Adaptive Immunity modules in the english-language Medical School as well as in the Italian-language BSc and MSc Medical Biotechnology courses. I also ran an elective course, designed to expose students to the uncertain and often contradictory arrangement of information in the scientific literature. In Humanitas University I teach modules on Adaptive Immunity (and closely related subjects) as part of an integrated course in the Medical Degree Course and the MedTech Degree Course (in english), as well as in the Nursing BSc Course and Nursing MSc Course (in italian). I also run an elective course on scientific communication.
Cardiovascular disease and cancer are key causes of morbidity and mortality, creating an urgent clinical need to develop novel therapeutic approaches. Inflammation and immune responses are implicated in the pathogenesis of many of these disorders. My lab is interested in deciphering the interactions between the adaptive immune system and different tissues during disease pathogenesis. We study the mechanisms underlying these interactions, from a systemic down to molecular level. We then utilize the findings to attempt innovative immunotherapies, and diagnostic/prognostic strategies for cardiovascular disease, cancer, and cancer immunotherapy-induced cardiotoxicity which may act as proof-of-principle for translation to the clinic. We are also currently studying the applications of these strategies to the cardiac comorbidities of COVID-19. Our work has received support from AIRC, the Italian Ministry of Health, the CARIPLO Foundation, the Veronesi Foundation, the Italian Ministry of Education, Universities and Research, Telethon and AriSLA. The adaptive immune system (composed of T cells and B cells) evolved in vertebrates, permitting the defense of the self against pathogens. Yet the evolution of mammalian pregnancy, which is dependent on recognition and active tolerization of paternally-derived fetal antigens during placental pregnancy (by Treg cells), may have brought about the evolution of key changes in how the adaptive immune system interacts with tissues in the mammalian body, in a manner optimized up to but not beyond the reproductively active age of the female (Aluvihare, Kallikourdis and Betz, Nature Immunology 2004; Kallikourdis, Canc Imm Immunother 2018; Martini et Front Immunol 2020). These non-optimal interactions between immunity and different tissues may have been exacerbated by the fact that in the last couple of centuries human lifespan has expanded substantially beyond the reproductively active age. The resultant non-optimal inflammation is implicated in the pathogenesis of cardiovascular disease, cancer and neurodegenerative disease, key causes of morbidity and mortality. In addition, it is linked to the problem of multimorbidity, the co-existence of diseases from the groups above. Adaptive Immunity and Cancer As an example of the application of the above rationale, we have recently demonstrated that pro-inflammatory T cells, which are used therapeutically to treat tumors, may be simultaneously mediating pro-tumoral effects (Garetto et al., 2016).
The identification and deciphering of this unexpected effect may pave the way for the refinement of current immunotherapeutic strategies for cancer. We are currently working on deciphering at a more systematic level how adaptive immunity affects cancer generation, growth and metastasis. Adaptive Immunity and Cardiovascular Disease We recently identified, via immunophenotyping at different stages of the disease, an association between the presence of pro-inflammatory T cells and heart failure (HF), both in experimental models and in human HF patient biopsies. On the basis of this finding, we utilized an FDA-approved drug that interferes with T cell function in order to treat experimentally-induced HF. Treatment resulted in a block of progression of HF, in a manner substantially more efficient than current standard drugs targeting cardiac disease (Kallikourdis et al, Nature Communications 2017; Martini et al, Circulation Research 2020). This innovative approach has been since hailed as “world-altering for the treatment of Cardiovascular Disease” (Simons et al, Nat Rev Cardiol 2019), and provided the mechanistic basis for a guideline on how to treat cardio-specific toxicity that occurs during checkpoint blockade cancer immunotherapy (Salem et al, N Engl J Med 2019). In searching for more detailed mechanistic explanations of the immune responses against the heart, we have now completed a single-cell RNASeq study of the cardiac immune infiltrate in Heart Failure (Martini et al, Circulation 2019). This generated insights on the mechanism of our abatacept-mediated therapy, on a mechanistic explanation for the lack of effects of anti-TNF clinical treatments in Heart Failure, and on the mechanism generating cardiac toxicity during tumor immunotherapy. We are currently extending our studies on the exciting new frontier of cardio-immunology, which promises to revolutionize how cardiac and vascular disease is treated.
- Martini E, Cremonesi M, Panico C, Carullo P, Bonfiglio CA, Serio S, Jachetti E, Colombo MP, Gianluigi Condorelli G* and Kallikourdis M* (2020) T Cell Costimulation Blockade Blunts Age-Related Heart Failure Circulation Res vol. 127, p. 1115-1117 doi: 10.1161/CIRCRESAHA.119.316530 (*:corresponding authors)
- Martini E, Giugliano S, Rescigno M, Kallikourdis M*. (2020) Regulatory T Cells Beyond Autoimmunity: From Pregnancy to Cancer and Cardiovascular Disease Front Immunol. 11:509. doi: 10.3389/fimmu.2020.00509. eCollection 2020. (*:corresponding author)
- Martini E, Kunderfranco P, Peano C, Carullo P, Cremonesi M, Schorn T, Carriero R, Termanini A, Colombo FS, Jachetti E, Panico C, Faggian G, Fumero A, Torracca L, Molgora M, Cibella J, Pagiatakis C, Brummelman J, Alvisi G, Mazza EMC, Colombo MP, Lugli E, Condorelli G*, Kallikourdis M*. (2019) Single cell sequencing of mouse heart immune infiltrate in pressure overload-driven heart failure reveals extent of immune activation Circulation 2019 Dec 17;140(25):2089-2107 doi:10.1161/CIRCULATIONAHA.119.041694.) (*:corresponding authors)
- Kallikourdis M*, Martini E, Carullo P, Sardi C, Roselli G, Greco C, Vignali D, Riva F, Ormbostad Berre AM, Stølen TO, Fumero A, Faggian G, Di Pasquale E, Elia L, Rumio C, Catalucci D, Papait R, Condorelli G* (2017) T cell costimulation blockade blunts pressure overload-induced heart failure. Nat. Commun. 8, 14680 doi: 10.1038/ncomms14680 (*:corresponding and co-supervising authors)
- Aluvihare V, Kallikourdis M and Betz A (2004) Regulatory T Cells Mediate Maternal Tolerance to the Fetus. Nat Immunol 5, 266-271. doi: 10.1038/ni1037