Matteo Riva

Bio: Matteo Riva is an academic researcher from Katholieke Universiteit Leuven. The author has contributed to research in topics: Immunotherapy & Myeloid-derived Suppressor Cell. The author has an hindex of 7, co-authored 20 publications receiving 322 citations. Previous affiliations of Matteo Riva include University of Milano-Bicocca & Université libre de Bruxelles.

Newcastle disease virotherapy induces long-term survival and tumor-specific immune memory in orthotopic glioma through the induction of immunogenic cell death.

Abstract: The oncolytic features of several naturally oncolytic viruses have been shown on Glioblastoma Multiforme cell lines and in xenotransplant models. However, orthotopic glioma studies in immunocompetent animals are lacking. Here we investigated Newcastle disease virus (NDV) in the orthotopic, syngeneic murine GL261 model. Seven days after tumor induction, mice received NDV intratumorally. Treatment significantly prolonged median survival and 50% of animals showed long-term survival. We demonstrated immunogenic cell death (ICD) induction in GL261 cells after NDV infection, comprising calreticulin surface exposure, release of HMGB1 and increased PMEL17 cancer antigen expression. Uniquely, we found absence of secreted ATP. NDV-induced ICD occurred independently of caspase signaling and was blocked by Necrostatin-1, suggesting the contribution of necroptosis. Autophagy induction following NDV infection of GL261 cells was demonstrated as well. In vivo, elevated infiltration of IFN-γ(+) T cells was observed in NDV-treated tumors, along with reduced accumulation of myeloid derived suppressor cells. The importance of a functional adaptive immune system in this paradigm was demonstrated in immunodeficient Rag2(-/-) mice and in CD8(+) T cell depleted animals, where NDV slightly prolonged survival, but failed to induce long-term cure. Secondary tumor induction with GL261 cells or LLC cells in mice surviving long-term after NDV treatment, demonstrated the induction of a long-term, tumor-specific immunological memory response by ND virotherapy. For the first time, we describe the therapeutic activity of NDV against GL261 tumors, evidenced in an orthotopic mouse model. The therapeutic effect relies on the induction of ICD in the tumor cells, which primes adaptive antitumor immunity.

Exploiting the Immunogenic Potential of Cancer Cells for Improved Dendritic Cell Vaccines.

Abstract: Cancer immunotherapy is currently the hottest topic in the oncology field, owing predominantly to the discovery of immune checkpoint blockers. These promising antibodies and their attractive combinatorial features have initiated the revival of other effective immunotherapies, such as dendritic cell (DC) vaccinations. Although DC-based immunotherapy can induce objective clinical and immunological responses in several tumor types, the immunogenic potential of this monotherapy is still considered suboptimal. Hence, focus should be directed on potentiating its immunogenicity by making step-by-step protocol innovations to obtain next-generation Th1-driving DC vaccines. We review some of the latest developments in the DC vaccination field, with a special emphasis on strategies that are applied to obtain a highly immunogenic tumor cell cargo to load and to activate the DCs. To this end, we discuss the effects of three immunogenic treatment modalities (ultraviolet light, oxidizing treatments, and heat shock) and five potent inducers of immunogenic cell death [radiotherapy, shikonin, high-hydrostatic pressure, oncolytic viruses, and (hypericin-based) photodynamic therapy] on DC biology and their application in DC-based immunotherapy in preclinical as well as clinical settings.

Myeloid Derived Suppressor Cells: Key Drivers of Immunosuppression in Ovarian Cancer.

Abstract: The presence of tumor infiltrating lymphocytes (TILs) is associated with a longer overall survival in advanced stage epithelial ovarian cancer. Despite the prognostic impact of TILs, response to checkpoint-inhibitors and antigen-specific active immunotherapy is limited in ovarian cancer. The goal of our study was to investigate the interaction between ovarian cancer and the innate and adaptive immune system in the ID8-fLuc syngeneic ovarian cancer mouse model. For the in vivo experiments C57BL/6, B6.129S7-Rag1tm1Mom/J, and B6.129P2(SJL)-Myd88tm1.1Defr/J mice were inoculated with ID8-fLuc. In vivo depletion experiments were performed using clodronate liposomes (CL), anti-CD8a, anti-GR1, anti-colony stimulating factor 1 (anti-CSF1), and TMβ1 (anti-CD122). Immune read out was performed by fluorescent activated cell sorting analysis for effector T cells, regulatory T cells, natural killer cells, B cells, macrophages, and myeloid derived suppressor cells (MDSC), immunohistochemistry for MDSC and tumor-associated macrophages (TAM) and immunofluorescence for M1 and M2 TAM in the vascular context. The effect of MDSC on T cell proliferation and phenotype were studied in vitro. We discovered that the absence of T and B cells did not influence tumor growth or survival of B6.129S7-Rag1tm1Mom/J mice compared to immunocompetent C57BL/6 mice. CL-induced macrophage depletion promoted tumor proliferation and shortened survival in C57BL/6 mice (p = 0.004) and in B6.129S7-Rag1tm1Mom/J mice (p = 0.0005). During CL treatment, we observed a clear increase of pro-inflammatory cytokines (p ≤ 0.02) and monocytic MDSC (p ≤ 0.01). Selective depletion of MDSC by anti-GR1 improved survival, certainly in comparison to mice treated with anti-CSF1 (p = 0.01-median survival 91 vs. 67.5 days). B6.129P2(SJL)-Myd88tm1.1Defr/J mice displayed to a longer median survival compared to C57BL/6 mice (90 vs. 76 days). MDSC activated by ID8-fLuc conditioned medium or ascites of tumor-bearing mice showed T cell suppressive functions in vitro. Based on these findings, we conclude that the adaptive immune system does not efficiently control tumor growth in the ID8-fLuc model. In addition, we discovered a prominent role for MDSC as the driver of immunosuppression in the ID8-fLuc ovarian cancer mouse model.

Indocyanine Green Videoangiography in Aneurysm Surgery: Systematic Review and Meta-Analysis.

Abstract: Background Although digital subtraction angiography (DSA) may be considered the gold standard for intraoperative vascular imaging, many neurosurgical centers rely only on indocyanine green videoangiography (ICG-VA) for the evaluation of clipping accuracy. Many studies have compared the results of ICG-VA with those of intraoperative DSA; however, a systematic review summarizing these results is still lacking. Objective To analyze the literature in order to evaluate ICG-VA accuracy in the identification of aneurysm remnants and vessel stenosis after aneurysm clipping. Methods We performed a systematic literature review of ICG-VA accuracy during aneurysm clipping as compared to microscopic visual observation (primary endpoint 1) and DSA (primary endpoint 2). Quality of studies was assessed with the QUADAS-2 tool. Meta-analysis was performed using a random effects model. Results The initial PubMed search resulted in 2871 records from January 2003 to April 2016; of these, 20 articles were eligible for primary endpoint 1 and 11 for primary endpoint 2. The rate of mis-clippings that eluded microscopic visual observation and were identified at ICG-VA was 6.1% (95% CI: 4.2-8.2), and the rate of mis-clippings that eluded ICG-VA and were identified at DSA was 4.5% (95% CI: 1.8-8.3). Conclusion Because a proportion of mis-clippings cannot be identified with ICG-VA, this technique should still be considered complementary rather than a replacement to DSA during aneurysm surgery. Incorporating other intraoperative tools, such as flowmetry or electrophysiological monitoring, can obviate the need for intraoperative DSA for the identification of vessel stenosis. Nevertheless, DSA likely remains the best tool for the detection of aneurysm remnants.

Human CD141(+) (BDCA-3)(+) dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens

Abstract: The characterization of human dendritic cell (DC) subsets is essential for the design of new vaccines. We report the first detailed functional analysis of the human CD141(+) DC subset. CD141(+) DCs are found in human lymph nodes, bone marrow, tonsil, and blood, and the latter proved to be the best source of highly purified cells for functional analysis. They are characterized by high expression of toll-like receptor 3, production of IL-12p70 and IFN-beta, and superior capacity to induce T helper 1 cell responses, when compared with the more commonly studied CD1c(+) DC subset. Polyinosine-polycytidylic acid (poly I:C)-activated CD141(+) DCs have a superior capacity to cross-present soluble protein antigen (Ag) to CD8(+) cytotoxic T lymphocytes than poly I:C-activated CD1c(+) DCs. Importantly, CD141(+) DCs, but not CD1c(+) DCs, were endowed with the capacity to cross-present viral Ag after their uptake of necrotic virus-infected cells. These findings establish the CD141(+) DC subset as an important functionally distinct human DC subtype with characteristics similar to those of the mouse CD8 alpha(+) DC subset. The data demonstrate a role for CD141(+) DCs in the induction of cytotoxic T lymphocyte responses and suggest that they may be the most relevant targets for vaccination against cancers, viruses, and other pathogens.

From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment (Review)

Abstract: The side effects of systemic chemotherapy used to treat cancer are often severe. For decades, oncologists have focused on treating the tumor, which may result in damage to the tumor-bearing host and its immune system. Recently, much attention has been paid to the immune system of patients and its activation via biological therapies. Biological therapies, including immunotherapy and oncolytic virus (OV) therapy, are often more physiological and well tolerated. The present review elucidated how these therapies work and why these therapies may be better tolerated: i) In contrast to chemotherapy, immunotherapies induce a memory function of the adaptive immunity system; ii) immunotherapies aim to specifically activate the immune system against cancer; side effects are low due to immune tolerance mechanisms, which maintain the integrity of the body in the presence of B and T lymphocytes with their antigen-receptor specificities and; iii) the type I interferon response, which is evoked by OVs, is an ancient innate immune defense system. Biological and physiological therapies, which support the immune system, may therefore benefit cancer treatment. The present review focused on immunotherapy, with the aim of reducing side effects and increasing long-lasting efficacy in cancer therapy.

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

Abstract: Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.

Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors.

Abstract: Conventional chemotherapeutics have been developed into clinically useful agents based on their ability to preferentially kill malignant cells, generally owing to their elevated proliferation rate. Nonetheless, the clinical activity of various chemotherapies is now known to involve the stimulation of anticancer immunity either by initiating the release of immunostimulatory molecules from dying cancer cells or by mediating off-target effects on immune cell populations. Understanding the precise immunological mechanisms that underlie the efficacy of chemotherapy has the potential not only to enable the identification of superior biomarkers of response but also to accelerate the development of synergistic combination regimens that enhance the clinical effectiveness of immune checkpoint inhibitors (ICIs) relative to their effectiveness as monotherapies. Indeed, accumulating evidence supports the clinical value of combining appropriately dosed chemotherapies with ICIs. In this Review, we discuss preclinical and clinical data on the immunostimulatory effects of conventional chemotherapeutics in the context of ICI-based immunotherapy.