Centro Interdipartimentale di Biotecnologie Molecolari "Guido Tarone"
Federica Cavallo PI
Full Professor of Immunology (General Pathology), University of Turin, Italy
Federica Riccardo Assistant Professor
Lidia Tarone Post-doctoral Fellow
Antonella Iacoviello Ph.D. Students
Irene Fiore Merighi Technician
Research activity
My team’s current research primarily focuses on the targeting of two antigens: the cystine/glutamate antiporter xCT and the other is the Chondroitin Sulfate Proteoglycan (CSPG)4. Cystine/glutamate antiporter xCT is vital for shielding cancer cells from oxidative stress. It is expressed by various tumor types, but it is also expressed by immune cells, influencing proliferation and effector function. To gain insight into the role of xCT, we generated xCTnull BALB/c mice for investigating its impact on the immune system. Additionally, HER2-transgenic mice were made xCTnull to study xCT in a mammary cancer-prone model. Mammary cancer cells derived from BALB-neuT/xCTnull mice and xCTKO cells were used to assess xCT’s contribution to malignant properties in vitro and in vivo. Our findings reveal that xCT disruption doesn’t prevent tumor initiation and growth but sensitizes cancer cells to oxidative stress, reducing cancer-cell metastasization to the lungs. This is accompanied by altered immune-cell recruitment in the pre-metastatic niche. This is accompanied by altered immune-cell recruitment in the pre-metastatic niche. Systemic xCT depletion in host mice doesn’t impact tumor growth, metastasis, or hinder proper humoral and cellular immune responses in vivo. We’ve developed various vaccination platforms (DNAbased, VLP-based, and Oncolytic-virus-based) to target xCT. These platforms effectively induce an immune response against xCT, mitigating the malignant features of mammary cancer cells expressing it. Overall, these results indicate that xCT isn’t essential for proper immune system function, supporting the safety of xCT targeting in oncology. Nevertheless, it plays a crucial role in processes vital to the metastatic seeding of mammary cancer cells, broadening the scope of xCT-targeting approaches (Figure 1).
Another promising target for immunotherapeutic interventions that we are studying is CSPG4. It has a limited expression in normal tissues and substantial overexpression in various tumor histotypes, where it regulates crucial cancer-related processes. Our research delves into DNA-based vaccination strategies targeting CSPG4 for treating challenging CSPG4-expressing tumors. While extensively characterized in malignant melanoma, our group has recently unveiled CSPG4 up-regulation and pivotal oncogenic role in osteosarcoma. However, being a self-antigen, CSPG4 is tolerated by the patient’s immune system, posing a significant obstacle to effective vaccine development. To overcome this challenge, our team has innovatively explored the concept of a chimeric CSPG4 vaccine, blending human and canine CSPG4 sequences. This approach aims to disrupt immune tolerance, triggering a robust anti-CSPG4 immune response capable of eliminating tumor cells and preventing recurrence and metastasis (Figure 2)
In recent years, my research group has been actively involved in evaluating the safety, immunogenicity, and clinical potential of this chimeric anti-CSPG4 vaccine. We conducted studies using preclinical mouse models of melanoma and osteosarcoma. Additionally, we explored its efficacy in client-owned dogs affected by spontaneous CSPG4+ melanoma and osteosarcoma, in collaboration with the Veterinary Teaching Hospital of the University of Turin. Interestingly, this canine model is considered highly predictive of the response to immunotherapy in humans.
We aim to advance the development of innovative combinatorial therapies targeting breast cancer, melanoma, and osteosarcoma to enhance patient outcomes. Our focus will be on investigating how xCT regulates ferroptosis, extracellular vesicle (EV) release, immunosuppression, and the formation of pre-metastatic niches. This knowledge will guide the development of combinatorial approaches involving xCT and immune checkpoint blockade (ICB), along with the establishment of an EV signature to predict ICB response in breast cancer. Concurrently, our research will delve into the role of CSPG4 in conventional therapy resistance. We plan to test anti-CSPG4 vaccination in conjunction with BRAF/MEK inhibitors and ICB for melanoma treatment. Additionally, we will explore its combination with chemotherapy and ‘non-conventional’ ICB for the management of osteosarcoma.
2023-2025: PRIN: PROGETTI DI RICERCA DI RILEVANTE INTERESSE NAZIONALE – Bando 2022, MUR.
2023-2024: Proof of Concept (PoC) – TOINPROVE/2023, University of Turin.
2022-2023: Research agreement, YGION Biomedical, Vienna, Austria.
2022-2023: Research agreement, ImmunoGenesis, Huston, Texas, US.
2022: Liberal contribution, Banca d’Italia.
2021-2022: PoC Instrument grant, University of Turin and Compagnia di San Paolo.
2019-2023: Investigator Grant, Fondazione AIRC per la Ricerca (AIRC IG 2018; ID 21468).
2019-2020: Research agreement, Indena S.p.A., Milano, Italy
Ruiu R, Cossu C, Iacoviello A, Conti L, Bolli E, Ponzone L, Magri J, Rumandla A, Calautti E, Cavallo F. Cystine/ glutamate antiporter xCT deficiency reduces metastasis without impairing immune system function in breast cancer mouse models. J Exp Clin Cancer Res. 2023. doi: 10.1186/s13046-023-02830-x.
Tarone L, Giacobino D, Camerino M, Maniscalco L, Iussich S, Parisi L, Giovannini G, Dentini A, Bolli E, Quaglino E, Merighi IF, Morello E, Buracco P, Riccardo F, Cavallo F. A chimeric human/dog-DNA vaccine against CSPG4 induces immunity with therapeutic potential in comparative preclinical models of osteosarcoma. Mol Ther. 2023. Doi: 10.1016/j.ymthe.2023.06.004. Epub ahead of print.
Riccardo F, Tarone L, Camerino M, Giacobino D, Iussich S, Barutello G, Arigoni M, Conti L, Bolli E, Quaglino E, Merighi IF, Morello E, Dentini A, Ferrone S, Buracco P, Cavallo F. Antigen mimicry as an effective strategy to induce CSPG4-targeted immunity in dogs with oral melanoma: a veterinary trial. J Immunother Cancer. 2022. Doi: 10.1136/jitc-2021-004007.
Rolih V, Caldeira J, Bolli E, Salameh A, Conti L, Barutello G, Riccardo F, Magri J, Lamolinara A, Parra K, Valenzuela P, Francia G, Iezzi M, Pericle F, Cavallo F. Development of a VLP-Based Vaccine Displaying an xCT Extracellular Domain for the Treatment of Metastatic Breast Cancer. Cancers (Basel). 2020. Doi: 10.3390/cancers12061492.
Riccardo F, Tarone L, Iussich S, Giacobino D, Arigoni M, Sammartano F, Morello E, Martano M, Gattino F, Maria R, Ferrone S, Buracco P, Cavallo F. Identification of CSPG4 as a promising target for translational combinatorial approaches in osteosarcoma. Ther Adv Med Oncol. 2019. Doi: 10.1177/1758835919855491.
Donofrio G, Tebaldi G, Lanzardo S, Ruiu R, Bolli E, Ballatore A, Rolih V, Macchi F, Conti L, Cavallo F. Bovine herpesvirus 4-based vector delivering the full length xCT DNA efficiently protects mice from mammary cancer metastases by targeting cancer stem cells. Oncoimmunology. 2018. Doi: 10.1080/2162402X.2018.1494108.
Bolli E, O’Rourke JP, Conti L, Lanzardo S, Rolih V, Christen JM, Barutello G, Forni M, Pericle F, Cavallo F. A Virus-Like-Particle immunotherapy targeting Epitope-Specifc anti-xCT expressed on cancer stem cell inhibits the progression of metastatic cancer in vivo. Oncoimmunology. 2017. Doi: 10.1080/2162402X.2017.1408746.
Tallerico R, Conti L, Lanzardo S, Sottile R, Garofalo C, Wagner AK, Johansson MH, Cristiani CM, Kärre K, Carbone E, Cavallo F. NK cells control breast cancer and related cancer stem cell hematological spread. Oncoimmunology. 2017. Doi: 10.1080/2162402X.2017.1284718.
Lanzardo S, Conti L, Rooke R, Ruiu R, Accart N, Bolli E, Arigoni M, Macagno M, Barrera G, Pizzimenti S, Aurisicchio L, Calogero RA, Cavallo F. Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer. Cancer Res. 2016. Doi: 10.1158/0008-5472.CAN-15-1208.
Riccardo F, Iussich S, Maniscalco L, Lorda Mayayo S, La Rosa G, Arigoni M, De Maria R, Gattino F, Lanzardo S, Lardone E, Martano M, Morello E, Prestigio S, Fiore A, Quaglino E, Zabarino S, Ferrone S, Buracco P, Cavallo F. CSPG4-specifc immunity and survival prolongation in dogs with oral malignant melanoma immunized with human CSPG4 DNA. Clin Cancer Res. 2014. Doi: 10.1158/1078-0432.CCR-13-3042.
