Kallikourdis Group

Contact Information

• Address
  Building C, Office C0.10
• Telephone
  02 8224 5212
• Fax
  02 8224 5101

ADAPTIVE IMMUNITY LABORATORY

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 have been recently 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 immunotherapy, 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.

To study the interactions between the adaptive immune system and different tissues during disease pathogenesis, we use novel techniques such as single cell Next Generation Sequencing, multi-parameter FACS, multi-parameter qPCR, tissue clarification, computational and quantitative analyses, retroviral and retrogenic technology, and 2-photon microscopy.

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.

Group Members

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  Marco Cremonesi View More