CalcinottoArianna Istituto Oncologico di Ricerca IORSwitzerland

Prof. Arianna Calcinotto, PhD is the Group Leader of the Cancer Immunotherapy laboratory at the Institute of Oncology Research (IOR) and assistant professor at USI in Switzerland. Leading a dynamic team focusing on the intricate interactions between cancer, bacteria, and immune cells in the tumor microenvironment, she has made pivotal contributions to elucidating the role of neutrophils in cancer and developing innovative immunotherapeutic strategies. This has culminated in the identification of numerous mechanisms by which aberrant neutrophil function in the tumor microenvironment contributes to cancer progression and treatment resistance. Prof. Calcinotto began her career earning her PhD in Molecular Medicine with honors from Vita-Salute San Raffaele University (Milan, Italy) in 2015, followed by postdoctoral training at the Mayo Clinic (Arizona, US) in the laboratory of Prof. Bergsagel and at the IOR in the laboratory of Prof. Alimonti. In 2018, she discovered a subset of immunosuppressive neutrophils that accumulate in prostate tumors during resistance to androgen deprivation therapy (castration-resistant prostate cancer, CRPC). These neutrophils promote therapeutic resistance via the production of IL-23 (Calcinotto et al. Nature 2018). This key finding led to a multicenter clinical trial in CRPC patients that successfully demonstrated the efficacy of a combined approach targeting neutrophils in conjunction with standard androgen deprivation therapy. Now, the Calcinotto lab has further challenged the long-held notion that neutrophils are short-lived cells by revealing that within the tumor microenvironment, they can acquire a senescent-like phenotype, persisting for extended periods and driving therapy resistance. By screening over 2,000 FDA-approved drugs, her team identified Romidepsin (an HDAC I inhibitor) as selectively capable of killing these persistent neutrophils, thereby slowing tumor progression in multiple preclinical models of both hormone-sensitive and castration-resistant prostate cancers (Bancaro et al Cancer Cell 2022). More recently, Prof. Calcinotto uncovered a novel population of tumor-associated neutrophil precursors (PreNeu) in high-risk breast cancer, characterized by an immature phenotype and the ability to proliferate. She demonstrated that these PreNeu release the oncometabolite succinate, which drives genomic instability in breast cancer cells and facilitates resistance to endocrine therapy. Critically, tumors infiltrated by PreNeu become sensitive to PARP inhibitors, such as olaparib, suggesting that this population of neutrophil precursors may serve as a biomarker to guide targeted treatment strategies (Mukherjee et al. Nature comm in press). Another significant aspect of her research involves the interplay between the gut microbiota and cancer. She demonstrated that certain bacteria drive the expansion of pro-tumorigenic Th17 cells, accelerating disease onset in mouse models of MM (Calcinotto et al. Nature comm 2018). She also identified bacterial species that produce dehydroepiandrosterone (DHEA), thus contributing to resistance to androgen deprivation therapy in prostate cancer (Pernigoni et al. Science 2021). Currently, the Calcinotto Lab is interested in understanding the pathogenic crosstalk between tumor cells, tissue-specific bacteria, and tumor-infiltrating immune cells in hormone-related tumor initiation, progression, and treatment-resistance to identify new, effective therapies for the treatment and prevention of cancer in individuals with germline BRCA mutations. With these goals, the group is synergizing its cancer immunology expertise with the IOSI (Istituto Oncologico della Svizzera Italiana), which has a long tradition of clinical oncology in breast and prostate cancers, with the final aim to apply these discoveries to the clinic, develop novel therapeutic options, and illuminate our understanding of the spectrum of interactions in the tumor microenvironment.