Publications by authors named "Matteo Bellone"

67 Publications

Anticancer innovative therapy congress: Highlights from the 10th anniversary edition.

Cytokine Growth Factor Rev 2021 Feb 14. Epub 2021 Feb 14.

Immunotherapy and Innovative Therapeutics Unit, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address:

During the Tenth Edition of the Annual Congress on "Anticancer Innovative Therapy" [Milan, 23/24 January 2020], experts in the fields of immuno-oncology, epigenetics, tumor cell signaling, and cancer metabolism shared their latest knowledge on the roles of i] epigenetics, and in particular, chromatin modifiers, ii] cancer metabolism, iii] cancer stem cells [CSCs], iv] tumor cell signaling, and iv] the immune system. The novel therapeutic approaches presented included epigenetic drugs, cell cycle inhibitors combined with ICB, antibiotics and other off-label drugs, small-molecules active against CSCs, liposome-delivered miRNAs, tumor-specific CAR-T cells, and T-cell-based immunotherapy. Moreover, important evidence on possible mechanisms of resistance to these innovative therapies were also discussed, in particular with respect to resistance to ICB. Overall, this conference provided scientists and clinicians with a broad overview of future challenges and hopes to improve cancer treatment reasonably in the medium-short term.
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http://dx.doi.org/10.1016/j.cytogfr.2021.02.001DOI Listing
February 2021

Much More Than IL-17A: Cytokines of the IL-17 Family Between Microbiota and Cancer.

Front Immunol 2020 10;11:565470. Epub 2020 Nov 10.

Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, I.R.C.C.S. Ospedale San Raffaele, Milan, Italy.

The interleukin-(IL-)17 family of cytokines is composed of six members named IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. IL-17A is the prototype of this family, and it was the first to be discovered and targeted in the clinic. IL-17A is essential for modulating the interplay between commensal microbes and epithelial cells at our borders (i.e., skin and mucosae), and yet, for protecting us from microbial invaders, thus preserving mucosal and skin integrity. Interactions between the microbiota and cells producing IL-17A have also been implicated in the pathogenesis of immune mediated inflammatory diseases and cancer. While interactions between microbiota and IL-17B-to-F have only partially been investigated, they are by no means less relevant. The cellular source of IL-17B-to-F, their main targets, and their function in homeostasis and disease distinguish IL-17B-to-F from IL-17A. Here, we intentionally overlook IL-17A, and we focus instead on the role of the other cytokines of the IL-17 family in the interplay between microbiota and epithelial cells that may contribute to cancer pathogenesis and immune surveillance. We also underscore differences and similarities between IL-17A and IL-17B-to-F in the microbiota-immunity-cancer axis, and we highlight therapeutic strategies that directly or indirectly target IL-17 cytokines in diseases.
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http://dx.doi.org/10.3389/fimmu.2020.565470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683804PMC
May 2021

Galectin-3 in Prostate Cancer Stem-Like Cells Is Immunosuppressive and Drives Early Metastasis.

Front Immunol 2020 10;11:1820. Epub 2020 Sep 10.

Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Galectin-3 (Gal-3) is an extracellular matrix glycan-binding protein with several immunosuppressive and pro-tumor functions. The role of Galectin-3 in cancer stem-like cells (CSCs) is poorly investigated. Here, we show that prostate CSCs also colonizing prostate-draining lymph nodes of transgenic adenocarcinoma of the mouse prostate (TRAMP) mice overexpress Gal-3. Gal-3 contributes to prostate CSC-mediated immune suppression because either Gal-3 silencing in CSCs, or co-culture of CSCs and T cells in the presence of the Gal-3 inhibitor N-Acetyl-D-lactosamine rescued T cell proliferation. N-Acetyl-D-lactosamine also rescued the proliferation of T cells in prostate-draining lymph nodes of TRAMP mice affected by prostate intraepithelial neoplasia. Additionally, Gal-3 impacted prostate CSC tumorigenic and metastatic potential , as Gal-3 silencing in prostate CSCs reduced both primary tumor growth and secondary invasion. Gal-3 was also found expressed in more differentiated prostate cancer cells, but with different intracellular distribution as compared to CSCs, which suggests different functions of Gal-3 in the two cell populations. In fact, the prevalent nuclear and cytoplasmic distribution of Gal-3 in prostate CSCs made them less susceptible to apoptosis, when compared to more differentiated prostate cancer cells, in which Gal-3 was predominantly intra-cytoplasmic. Finally, we found Gal-3 expressed in human and mouse prostate intraepithelial neoplasia lesions and in metastatic lymph nodes. All together, these findings identify Gal-3 as a key molecule and a potential therapeutic target already in the early phases of prostate cancer progression and metastasis.
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http://dx.doi.org/10.3389/fimmu.2020.01820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516304PMC
April 2021

ACE polymorphisms and COVID-19-related mortality in Europe.

J Mol Med (Berl) 2020 11 15;98(11):1505-1509. Epub 2020 Sep 15.

I.R.C.C.S. Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy.

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http://dx.doi.org/10.1007/s00109-020-01981-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491982PMC
November 2020

Iron Induces Cell Death and Strengthens the Efficacy of Antiandrogen Therapy in Prostate Cancer Models.

Clin Cancer Res 2020 Dec 14;26(23):6387-6398. Epub 2020 Sep 14.

Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Purpose: In search of novel strategies to improve the outcome of advanced prostate cancer, we considered that prostate cancer cells rearrange iron homeostasis, favoring iron uptake and proliferation. We exploited this adaptation by exposing prostate cancer preclinical models to high-dose iron to induce toxicity and disrupt adaptation to androgen starvation.

Experimental Design: We analyzed markers of cell viability and mechanisms underlying iron toxicity in androgen receptor-positive VCaP and LNCaP, castration-resistant DU-145 and PC-3, and murine TRAMP-C2 cells treated with iron and/or the antiandrogen bicalutamide. We validated the results in VCaP and PC-3 xenografts and in TRAMP-C2 injected mice treated with iron and/or bicalutamide.

Results: Iron was toxic for all prostate cancer cells. In particular, VCaP, LNCaP, and TRAMP-C2 were highly iron sensitive. Toxicity was mediated by oxidative stress, which primarily affected lipids, promoting ferroptosis. In highly sensitive cells, iron additionally caused protein damage. High-basal iron content and oxidative status defined high iron sensitivity. Bicalutamide-iron combination exacerbated oxidative damage and cell death, triggering protein oxidation also in poorly iron-sensitive DU-145 and PC-3 cells., iron reduced tumor growth in TRAMP-C2 and VCaP mice. In PC-3 xenografts, bicalutamide-iron combination caused protein oxidation and successfully impaired tumor expansion while single compounds were ineffective. Macrophages influenced body iron distribution but did not limit the iron effect on tumor expansion.

Conclusions: Our models allow us to dissect the direct iron effect on cancer cells. We demonstrate the proof of principle that iron toxicity inhibits prostate cancer cell proliferation, proposing a novel tool to strengthen antiandrogen treatment efficacy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3182DOI Listing
December 2020

Microbiota-Propelled T Helper 17 Cells in Inflammatory Diseases and Cancer.

Microbiol Mol Biol Rev 2020 05 4;84(2). Epub 2020 Mar 4.

Molekulare Immunologie und Gastroenterologie I, Medizinische Klinik und Poliklink, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.

Technologies allowing genetic sequencing of the human microbiome are opening new realms to discovery. The host microbiota substantially impacts immune responses both in immune-mediated inflammatory diseases (IMIDs) and in tumors affecting tissues beyond skin and mucosae. However, a mechanistic link between host microbiota and cancer or IMIDs has not been well established. Here, we propose T helper 17 (T17) lymphocytes as the connecting factor between host microbiota and rheumatoid or psoriatic arthritides, multiple sclerosis, breast or ovarian cancer, and multiple myeloma. We theorize that similar mechanisms favor the expansion of gut-borne T17 cells and their deployment at the site of inflammation in extraborder IMIDs and tumors, where T17 cells are driving forces. Thus, from a pathogenic standpoint, tumors may share mechanistic routes with IMIDs. A review of similarities and divergences in microbiota-T17 cell interactions in IMIDs and cancer sheds light on previously ignored pathways in either one of the two groups of pathologies and identifies novel therapeutic avenues.
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http://dx.doi.org/10.1128/MMBR.00064-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062199PMC
May 2020

Boosting Interleukin-12 Antitumor Activity and Synergism with Immunotherapy by Targeted Delivery with isoDGR-Tagged Nanogold.

Small 2019 11 16;15(45):e1903462. Epub 2019 Sep 16.

Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy.

The clinical use of interleukin-12 (IL12), a cytokine endowed with potent immunotherapeutic anticancer activity, is limited by systemic toxicity. The hypothesis is addressed that gold nanoparticles tagged with a tumor-homing peptide containing isoDGR, an αvβ3-integrin binding motif, can be exploited for delivering IL12 to tumors and improving its therapeutic index. To this aim, gold nanospheres are functionalized with the head-to-tail cyclized-peptide CGisoDGRG (Iso1) and murine IL12. The resulting nanodrug (Iso1/Au/IL12) is monodispersed, stable, and bifunctional in terms of αvβ3 and IL12-receptor recognition. Low-dose Iso1/Au/IL12, equivalent to 18-75 pg of IL12, induces antitumor effects in murine models of fibrosarcomas and mammary adenocarcinomas, with no evidence of toxicity. Equivalent doses of Au/IL12 (a nanodrug lacking Iso1) fail to delay tumor growth, whereas 15 000 pg of free IL12 is necessary to achieve similar effects. Iso1/Au/IL12 significantly increases tumor infiltration by innate immune cells, such as NK and iNKT cells, monocytes, and neutrophils. NK cell depletion completely inhibits its antitumor effects. Low-dose Iso1/Au/IL12 can also increase the therapeutic efficacy of adoptive T-cell therapy in mice with autochthonous prostate cancer. These findings indicate that coupling IL12 to isoDGR-tagged nanogold is a valid strategy for enhancing its therapeutic index and sustaining adoptive T-cell therapy.
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http://dx.doi.org/10.1002/smll.201903462DOI Listing
November 2019

Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival.

J Immunother Cancer 2019 07 31;7(1):201. Epub 2019 Jul 31.

Department of Medicine and Sciences of Aging, G. d'Annunzio University of Chieti-Pescara, Via L. Polacchi 11, 66100, Chieti, Italy.

Background: Interleukin(IL)-30/IL-27p28 production by Prostate Cancer (PC) Stem-Like Cells (SLCs) has proven, in murine models, to be critical to tumor onset and progression. In PC patients, IL-30 expression by leukocytes infiltrating PC and draining lymph nodes correlates with advanced disease grade and stage. Here, we set out to dissect the role of host immune cell-derived IL-30 in PC growth and patient outcome.

Methods: PC-SLCs were implanted in wild type (WT) and IL-30 conditional knockout (IL-30KO) mice. Histopathological and cytofluorimetric analyses of murine tumors and lymphoid tissues prompted analyses of patients' PC samples and follow-ups.

Results: Implantation of PC-SLCs in IL-30KO mice, gave rise to slow growing tumors characterized by apoptotic events associated with CD4T lymphocyte infiltrates and lack of CD4Foxp3 T regulatory cells (Tregs). IL-30 knockdown in PC-SLCs reduced cancer cell proliferation, vascularization and intra-tumoral Indoleamine 2,3-Dioxygenase (IDO)CD11bGr-1 myeloid-derived cells (MDCs) and led to a significant delay in tumor growth and increase in survival. IL-30-silenced tumors developed in IL-30KO mice, IL-30tumors, lacked vascular supply and displayed frequent apoptotic cancer cells entrapped by perforinTRAILCD3Tlymphocytes, most of which had a CD4T phenotype, whereas IL-10TGFβFoxp3Tregs were lacking. IL-30 silencing in PC-SLCs prevented lung metastasis in 73% of tumor-bearing WT mice and up to 80% in tumor-bearing IL-30KO mice. In patients with high-grade and locally advanced PC, those with IL-30tumors, showed distinct intra-tumoral cytotoxic granule-associated RNA binding protein (TIA-1)CD4Tlymphocyte infiltrate, rare Foxp3Tregs and a lower biochemical recurrence rate compared to patients with IL-30tumors in which IL-30 is expressed in both tumor cells and infiltrating leukocytes.

Conclusion: The lack of host leukocyte-derived IL-30 inhibits Tregs expansion, promotes intra-tumoral infiltration of CD4T lymphocytes and cancer cell apoptosis. Concomitant lack of MDC influx, obtained by IL-30 silencing in PC-SLCs, boosts cytotoxic T lymphocyte activation and cancer cell apoptosis resulting in a synergistic tumor suppression with the prospective benefit of better survival for patients with advanced disease.
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http://dx.doi.org/10.1186/s40425-019-0668-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670138PMC
July 2019

Homotypic and Heterotypic Activation of the Notch Pathway in Multiple Myeloma-Enhanced Angiogenesis: A Novel Therapeutic Target?

Neoplasia 2019 01 5;21(1):93-105. Epub 2018 Dec 5.

Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.

Interactions of multiple myeloma (MM) cells with endothelial cells (ECs) enhance angiogenesis and MM progression. Here, we investigated the role of Notch signaling in the cross talk between ECs and MM cells enabling angiogenesis. MMECs showed higher expression of Jagged1/2 ligands, of activated Notch1/2 receptors, and of Hes1/Hey1 Notch target genes than ECs from monoclonal gammopathy of undetermined significance patients, suggesting that homotypic activation of Notch pathway occurs in MM. MM cells co-cultured with MMECs triggered Notch activation in these cells through a cell-to-cell contact-dependent way via Jagged1/2, resulting in Hes1/Hey1 overexpression. The angiogenic effect of Notch pathway was analyzed through Notch1/2·siRNAs and the γ-secretase inhibitor MK-0752 by in vitro (adhesion, migration, chemotaxis, angiogenesis) and in vivo (Vk12598/C57B/6 J mouse model) studies. Activated Notch1/2 pathway was associated with the overangiogenic MMEC phenotype: Notch1/2 knockdown or MK-0752 treatment reduced Hes1/Hey1 expression, impairing in vitro angiogenesis of both MMECs alone and co-cultured with MM cells. MM cells were unable to restore angiogenic abilities of treated MMECs, proving that MMEC angiogenic activities closely rely on Notch pathway. Furthermore, Notch1/2 knockdown affected VEGF/VEGFR2 axis, indicating that the Notch pathway interferes with VEGF-mediated control on angiogenesis. MK-0752 reduced secretion of proangiogenic/proinflammatory cytokines in conditioned media, thus inhibiting blood vessel formation in the CAM assay. In the Vk12598/C57B/6 J mouse, MK-0752 treatment restrained angiogenesis by reducing microvessel density. Overall, homotypic and heterotypic Jagged1/2-mediated Notch activation enhances MMECs angiogenesis. Notch axis inhibition blocked angiogenesis in vitro and in vivo, suggesting that the Notch pathway may represent a novel therapeutic target in MM.
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http://dx.doi.org/10.1016/j.neo.2018.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282459PMC
January 2019

Microbiota-driven interleukin-17-producing cells and eosinophils synergize to accelerate multiple myeloma progression.

Nat Commun 2018 12 3;9(1):4832. Epub 2018 Dec 3.

Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, 20132, Italy.

The gut microbiota has been causally linked to cancer, yet how intestinal microbes influence progression of extramucosal tumors is poorly understood. Here we provide evidence implying that Prevotella heparinolytica promotes the differentiation of Th17 cells colonizing the gut and migrating to the bone marrow (BM) of transgenic Vk*MYC mice, where they favor progression of multiple myeloma (MM). Lack of IL-17 in Vk*MYC mice, or disturbance of their microbiome delayed MM appearance. Similarly, in smoldering MM patients, higher levels of BM IL-17 predicted faster disease progression. IL-17 induced STAT3 phosphorylation in murine plasma cells, and activated eosinophils. Treatment of Vk*MYC mice with antibodies blocking IL-17, IL-17RA, and IL-5 reduced BM accumulation of Th17 cells and eosinophils and delayed disease progression. Thus, in Vk*MYC mice, commensal bacteria appear to unleash a paracrine signaling network between adaptive and innate immunity that accelerates progression to MM, and can be targeted by already available therapies.
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http://dx.doi.org/10.1038/s41467-018-07305-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277390PMC
December 2018

Immune Checkpoint-Mediated Interactions Between Cancer and Immune Cells in Prostate Adenocarcinoma and Melanoma.

Front Immunol 2018 31;9:1786. Epub 2018 Jul 31.

Cellular Immunology Unit, Department of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.

Prostate adenocarcinoma (PCa) and melanoma are paradigmatic examples of tumors that are either poorly or highly sensitive to therapies based on monoclonal antibodies directed against regulatory pathways in T lymphocytes [i.e., immune checkpoint blockade (ICB)]. Yet, approximately 40% of melanoma patients are resistant or acquire resistance to ICB. What characterize the microenvironment of PCa and ICB-resistant melanoma are a scanty cytotoxic T cell infiltrate and a strong immune suppression, respectively. Here, we compare the tumor microenvironment in these two subgroups of cancer patients, focusing on some among the most represented immune checkpoint molecules: cytotoxic T lymphocyte-associated antigen-4, programmed death-1, lymphocyte activation gene-3, and T cell immunoglobulin and mucin-domain containing-3. We also report on several examples of crosstalk between cancer and immune cells that are mediated by inhibitory immune checkpoints and identify promising strategies aimed at overcoming ICB resistance both in PCa and melanoma.
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http://dx.doi.org/10.3389/fimmu.2018.01786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079266PMC
September 2019

Bimodal CD40/Fas-Dependent Crosstalk between iNKT Cells and Tumor-Associated Macrophages Impairs Prostate Cancer Progression.

Cell Rep 2018 03;22(11):3006-3020

Experimental Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan 20123, Italy. Electronic address:

Heterotypic cellular and molecular interactions in the tumor microenvironment (TME) control cancer progression. Here, we show that CD1d-restricted invariant natural killer (iNKT) cells control prostate cancer (PCa) progression by sculpting the TME. In a mouse PCa model, iNKT cells restrained the pro-angiogenic and immunosuppressive capabilities of tumor-infiltrating immune cells by reducing pro-angiogenic TIE2, M2-like macrophages (TEMs), and sustaining pro-inflammatory M1-like macrophages. iNKT cells directly contacted macrophages in the PCa stroma, and iNKT cell transfer into tumor-bearing mice abated TEMs, delaying tumor progression. iNKT cells modulated macrophages through the cooperative engagement of CD1d, Fas, and CD40, which promoted selective killing of M2-like and survival of M1-like macrophages. Human PCa aggressiveness associate with reduced intra-tumoral iNKT cells, increased TEMs, and expression of pro-angiogenic genes, underscoring the clinical significance of this crosstalk. Therefore, iNKT cells may control PCa through mechanisms involving differential macrophage modulation, which may be harnessed for therapeutically reprogramming the TME.
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http://dx.doi.org/10.1016/j.celrep.2018.02.058DOI Listing
March 2018

Targeting Tumor Vasculature with TNF Leads Effector T Cells to the Tumor and Enhances Therapeutic Efficacy of Immune Checkpoint Blockers in Combination with Adoptive Cell Therapy.

Clin Cancer Res 2018 05 28;24(9):2171-2181. Epub 2018 Feb 28.

Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Irregular blood flow and endothelial cell anergy, which characterize many solid tumors, hinder tumor infiltration by cytotoxic T lymphocytes (CTL). This confers resistance to cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes (i.e., immune checkpoint blockade, ICB). We investigated whether NGR-TNF, a TNF derivative capable of targeting the tumor vasculature, and improving intratumor infiltration by activated CTLs, could sensitize tumors to ICB with antibodies specific for the PD-1 and CTLA-4 receptors. Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with autochthonous prostate cancer and C57BL/6 mice with orthotopic B16 melanoma were treated with NGR-TNF, adoptive T-cell therapy (ACT), and ICB, and monitored for immune surveillance and disease progression. The combination of ACT, NGR-TNF, and ICB was the most effective in delaying disease progression, and in improving overall survival of mice bearing ICB-resistant prostate cancer or melanoma. Mechanistically, the therapeutic effects were associated with potent tumor infiltration, especially by endogenous but also by adoptively transferred PD-1, granzyme B, and interferon-γ CTLs. The therapeutic effects were also associated with favorable T-effector/regulatory T cell ratios. Targeting the tumor vasculature with low-dose TNF in association with ACT may represent a novel strategy for enhancing T-cell infiltration in tumors and overcoming resistance to immune checkpoint blockers. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2210DOI Listing
May 2018

Interleukin-30/IL27p28 Shapes Prostate Cancer Stem-like Cell Behavior and Is Critical for Tumor Onset and Metastasization.

Cancer Res 2018 05 27;78(10):2654-2668. Epub 2018 Feb 27.

Division of Anatomic Pathology, "SS Annunziata" Hospital, Chieti, Italy.

Prostate cancer stem-like cells (PCSLC) are believed to be responsible for prostate cancer onset and metastasis. Autocrine and microenvironmental signals dictate PCSLC behavior and patient outcome. In prostate cancer patients, IL30/IL27p28 has been linked with tumor progression, but the mechanisms underlying this link remain mostly elusive. Here, we asked whether IL30 may favor prostate cancer progression by conditioning PCSLCs and assessed the value of blocking IL30 to suppress tumor growth. IL30 was produced by PCSLCs in human and murine prostatic intraepithelial neoplasia and displayed significant autocrine and paracrine effects. PCSLC-derived IL30 supported PCSLC viability, self-renewal and tumorigenicity, expression of inflammatory mediators and growth factors, tumor immune evasion, and regulated chemokine and chemokine receptor genes, primarily via STAT1/STAT3 signaling. IL30 overproduction by PCSLCs promoted tumor onset and development associated with increased proliferation, vascularization, and myeloid cell recruitment. Furthermore, it promoted PCSLC dissemination to lymph nodes and bone marrow by upregulating the CXCR5/CXCL13 axis, and drove metastasis to lungs through the CXCR4/CXCL12 axis. These mechanisms were drastically hindered by IL30 knockdown or knockout in PCSLCs. Collectively, these results mark IL30 as a key driver of PCSLC behavior. Targeting IL30 signaling may be a potential therapeutic strategy against prostate cancer progression and recurrence. IL30 plays an important role in regulating prostate cancer stem-like cell behavior and metastatic potential, therefore targeting this cytokine could hamper prostate cancer progression or recurrence. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-3117DOI Listing
May 2018

Osteopontin and the immune system: another brick in the wall.

Cell Mol Immunol 2018 Apr 2;15(4):405-407. Epub 2017 Oct 2.

Cellular Immunology Unit, Department of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132, Milan, Italy.

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http://dx.doi.org/10.1038/cmi.2017.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052835PMC
April 2018

PD-L1 Expression and CD8 T-cell Infiltrate are Associated with Clinical Progression in Patients with Node-positive Prostate Cancer.

Eur Urol Focus 2019 03 21;5(2):192-196. Epub 2017 Jun 21.

NET-IMPACT, IRCCS Ospedale San Raffaele, Milan, Italy; Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy. Electronic address:

Prostate cancer (PCa) patients with lymph node invasion at radical prostatectomy are at higher risk of tumor recurrence and receive immediate androgen deprivation therapy (ADT). While approximately 30% of these patients do not experience recurrence, others experience disease recurrence despite ADT, and currently no biomarkers can accurately identify them. We analyzed tumors from 51 patients with node-positive prostate cancer using immunohistochemistry to investigate whether expression of the immune checkpoint ligand PD-L1 by tumor cells or the density of CD8 or CD20 cells are associated with clinical progression. Patients with at least 1% PD-L1 tumor cells had shorter metastasis-free survival than those with PD-L1 tumors (p=0.008, log-rank test). Univariate Cox regression showed that patients with PD-L1 tumors had almost four times the risk of experiencing distant metastases than those with PD-L1 tumors (hazard ratio 3.90). In addition, we found that PD-L1 expression was significantly associated with CD8 T-cell density, but not with CD20 B-cell density. While these results need to be confirmed in larger studies, they show that PD-L1 and CD8 may be used as biomarkers for node-positive patients at high risk of progression. The study also provides a rationale for selecting patients with node-positive PCa who might benefit the most from adjuvant immunotherapies. PATIENT SUMMARY: None of the available biomarkers can identify node-positive prostate cancer that will recur after surgery. We found that expression of PD-L1 by tumor cells and a high density of CD8 T cells in tumor are associated with a higher risk of clinical progression in men with node-positive prostate cancer.
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http://dx.doi.org/10.1016/j.euf.2017.05.013DOI Listing
March 2019

Fatty is not that bad: feeding short-chain fatty acids to restrain autoimmunity.

Cell Mol Immunol 2017 Jul 17. Epub 2017 Jul 17.

Department of Immunology, Transplantation and Infectious Diseases, Cellular Immunology Unit, San Raffaele Scientific Institute, Milan 20132, Italy.

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http://dx.doi.org/10.1038/cmi.2017.52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675955PMC
July 2017

Goals and objectives of the Italian Network for Tumor Biotherapy (NIBIT).

Cytokine Growth Factor Rev 2017 08 16;36:1-3. Epub 2017 Jun 16.

Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCSS San Raffaele Scientific Institute, Milan, Italy.

The explosion in the immuno-oncology field, exemplified by the clinical implementation of immune checkpoint inhibitor blockade and other immunotherapeutic strategies was quickly recognized by the Italian biomedical community, thanks to the networking activities of the Italian Network for Tumor Biotherapy (NIBIT), which has been active since 2004 in the diffusion of new scientific and clinical findings in the fields of tumor immunology and immunotherapy. Numerous activities of NIBIT have also helped to overcome the hurdles associated with the clinical implementation of cancer immune-biotherapeutic strategies at the national and international levels. Looking forward, a concerted interaction of NIBIT with existing European networks focused on cancer bio-immunotherapy will further contribute to the development of improved therapies in the immuno-oncology field. This Introduction briefly summarizes the history and objectives of NIBIT, as well as the current activities of the Network.
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http://dx.doi.org/10.1016/j.cytogfr.2017.06.004DOI Listing
August 2017

Constitutive and acquired mechanisms of resistance to immune checkpoint blockade in human cancer.

Cytokine Growth Factor Rev 2017 08 2;36:17-24. Epub 2017 Jun 2.

San Raffaele Scientific Institute, 20132 Milan, Italy.

Cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes has been revolutionizing medical oncology, and the clinical success of monoclonal antibodies targeting either cytotoxic T lymphocyte antigen-4 (CTLA-4) or program death-1 (PD-1) in patients affected by melanoma, Hodgkin's lymphoma, Merkel cell carcinoma, and head and neck, bladder, renal cell or non-small cell lung cancer is way beyond the most optimistic expectation. However, immune checkpoint blockade (ICB) has failed to arrest progression in a consistent amount of patients affected by those tumors, and various histological types, including breast, colon and prostate cancer, are less sensitive to this therapeutic approach. Such clinical findings have fueled massive research efforts in the attempt to identify pre-existing and acquired mechanisms of resistance to ICB. Here we focus on evidences emerging from studies in humans on how tumor cells and the tumor microenvironment contribute to the heterogeneous clinical responses, and we propose strategies stemming from pre-clinical models that might improve clinical outcomes for patients.
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http://dx.doi.org/10.1016/j.cytogfr.2017.06.002DOI Listing
August 2017

Invariant NKT cells contribute to chronic lymphocytic leukemia surveillance and prognosis.

Blood 2017 06 2;129(26):3440-3451. Epub 2017 May 2.

Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.

Chronic lymphocytic leukemia (CLL) is characterized by the expansion of malignant CD5 B lymphocytes in blood, bone marrow, and lymphoid organs. CD1d-restricted invariant natural killer T (iNKT) cells are innate-like T lymphocytes strongly implicated in tumor surveillance. We investigated the impact of iNKT cells in the natural history of the disease in the Eμ-Tcl1 (Tcl1) CLL mouse model and 68 CLL patients. We found that Tcl1-CLL cells express CD1d and that iNKT cells critically delay disease onset but become functionally impaired upon disease progression. In patients, disease progression correlates with high CD1d expression on CLL cells and impaired iNKT cells. Conversely, disease stability correlates with negative or low CD1d expression on CLL cells and normal iNKT cells, suggesting indirect leukemia control. iNKT cells indeed hinder CLL survival in vitro by restraining CD1d-expressing nurse-like cells, a relevant proleukemia macrophage population. Multivariable analysis identified iNKT cell frequency as an independent predictor of disease progression. Together, these results support the contribution of iNKT cells to CLL immune surveillance and highlight iNKT cell frequency as a prognostic marker for disease progression.
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http://dx.doi.org/10.1182/blood-2016-11-751065DOI Listing
June 2017

Imatinib Spares cKit-Expressing Prostate Neuroendocrine Tumors, whereas Kills Seminal Vesicle Epithelial-Stromal Tumors by Targeting PDGFR-β.

Mol Cancer Ther 2017 02 15;16(2):365-375. Epub 2016 Dec 15.

Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Prostate cancer is a leading cause of cancer-related death in males worldwide. Indeed, advanced and metastatic disease characterized by androgen resistance and often associated with neuroendocrine (NE) differentiation remains incurable. Using the spontaneous prostate cancer TRAMP model, we have shown that mast cells (MCs) support in vivo the growth of prostate adenocarcinoma, whereas their genetic or pharmacologic targeting favors prostate NE cancer arousal. Aiming at simultaneously targeting prostate NE tumor cells and MCs, both expressing the cKit tyrosine kinase receptor, we have tested the therapeutic effect of imatinib in TRAMP mice. Imatinib-treated TRAMP mice experience a partial benefit against prostate adenocarcinoma, because of inhibition of supportive MCs. However, they show an unexpected outgrowth of prostate NE tumors, likely because of defective signaling pathway downstream of cKit receptor. Also unexpected but very effective was the inhibition of epithelial-stromal tumors of the seminal vesicles achieved by imatinib treatment. These tumors normally arise in the seminal vesicles of TRAMP mice, independently of the degree of prostatic glandular lesions, and resemble phyllodes tumors found in human prostate and seminal vesicles, and in breast. In both mice and in patients, these tumors are negative for cKit but express PDGFR-β, another tyrosine kinase receptor specifically inhibited by imatinib. Our results imply a possible detrimental effect of imatinib in prostate cancer patients but suggest a promising therapeutic application of imatinib in the treatment of recurrent or metastatic phyllodes tumors. Mol Cancer Ther; 16(2); 365-75. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0466DOI Listing
February 2017

T Cells Redirected to a Minor Histocompatibility Antigen Instruct Intratumoral TNFα Expression and Empower Adoptive Cell Therapy for Solid Tumors.

Cancer Res 2017 02 21;77(3):658-671. Epub 2016 Nov 21.

Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.

Donor-derived allogeneic T cells evoke potent graft versus tumor (GVT) effects likely due to the simultaneous recognition of tumor-specific and host-restricted minor histocompatibility (H) antigens. Here we investigated whether such effects could be reproduced in autologous settings by TCR gene-engineered lymphocytes. We report that T cells redirected either to a broadly expressed Y-encoded minor H antigen or to a tumor-associated antigen, although poorly effective if individually transferred, when simultaneously administered enabled acute autochthonous tumor debulking and resulted in durable clinical remission. Y-redirected T cells proved hyporesponsive in peripheral lymphoid organs, whereas they retained effector function at the tumor site, where in synergy with tumor-redirected lymphocytes, they instructed TNFα expression, endothelial cell activation, and intratumoral T-cell infiltration. While neutralizing TNFα hindered GVT effects by the combined T-cell infusion, a single injection of picogram amounts of NGR-TNF, a tumor vessel-targeted TNFα derivative currently in phase III clinical trials, substituted for Y-redirected cells and enabled tumor debulking by tumor-redirected lymphocytes. Together, our results provide new mechanistic insights into allogeneic GVT, validate the importance of targeting the tumor and its associated stroma, and prove the potency of a novel combined approach suitable for immediate clinical implementation. Cancer Res; 77(3); 658-71. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0725DOI Listing
February 2017

Long non-coding RNAs as novel therapeutic targets in cancer.

Pharmacol Res 2016 08 19;110:131-138. Epub 2016 May 19.

San Raffaele Scientific Institute, Cellular Immunology Unit, Milan, Italy.

Thanks to impressive technology advancements, pervasive expression of non-coding RNAs (ncRNAs) has been recently identified in the genome of numerous cancers. Long ncRNAs (lncRNAs) belong to a new class of ncRNAs including tens of thousands different species. A fraction of these molecules shows a striking cancer-enriched expression pattern, suggesting an essential role in tumor cells and, possibly, a utility in therapeutic terms. This review aims at summarizing current knowledge for the identification and validation of lncRNAs as therapeutics targets in tumors. Both in-silico and wet-biology resources are presented in relation to the many challenges that the scientific community still needs to address in terms of lncRNA identification, stratification, patient personalization, drug delivery and toxicity.
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http://dx.doi.org/10.1016/j.phrs.2016.05.018DOI Listing
August 2016

Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients.

Cancer Res 2016 04 11;76(7):1781-91. Epub 2016 Feb 11.

Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy. Università Vita-Salute San Raffaele, Milan, Italy.

Angiogenesis has been postulated to be critical for the pathogenesis of multiple myeloma, a neoplastic disease characterized by abnormal proliferation of malignant plasma cells in the bone marrow (BM). Cleavage of the N- and C-terminal regions of circulating chromogranin A (CgA, CHGA), classically an antiangiogenic protein, can activate latent antiangiogenic and proangiogenic sites, respectively. In this study, we investigated the distribution of CgA-derived polypeptides in multiple myeloma patients and the subsequent implications for disease progression. We show that the ratio of pro/antiangiogenic forms of CgA is altered in multiple myeloma patients compared with healthy subjects and that this ratio is higher in BM plasma compared with peripheral plasma, suggesting enhanced local cleavage of the CgA C-terminal region. Enhanced cleavage correlated with increased VEGF and FGF2 BM plasma levels and BM microvascular density. Using the Vk*MYC mouse model of multiple myeloma, we further demonstrate that exogenously administered CgA was cleaved in favor of the proangiogenic form and was associated with increased microvessel density. Mechanistic studies revealed that multiple myeloma and proliferating endothelial cells can promote CgA C-terminal cleavage by activating the plasminogen activator/plasmin system. Moreover, cleaved and full-length forms could also counter balance the pro/antiangiogenic activity of each other in in vitro angiogenesis assays. These findings suggest that the CgA-angiogenic switch is activated in the BM of multiple myeloma patients and prompt further investigation of this CgA imbalance as a prognostic or therapeutic target. Cancer Res; 76(7); 1781-91. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1637DOI Listing
April 2016

Immunosuppression via Tenascin-C.

Oncoscience 2015 21;2(8):667-8. Epub 2015 Aug 21.

Division of Immunology, Transplantation and Infectious Diseases, Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580052PMC
http://dx.doi.org/10.18632/oncoscience.210DOI Listing
October 2015

Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma.

Oncoimmunology 2015 Jun 7;4(6):e1008850. Epub 2015 May 7.

Cellular Immunology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy.

While multiple myeloma (MM) is almost invariably preceded by asymptomatic monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM), the alterations of the bone marrow (BM) microenvironment that establish progression to symptomatic disease are circumstantial. Here we show that in Vk*MYC mice harboring oncogene-driven plasma cell proliferative disorder, disease appearance associated with substantial modifications of the BM microenvironment, including a progressive accumulation of both CD8 and CD4 T cells with a dominant T helper type 1 (Th1) response. Progression from asymptomatic to symptomatic MM was characterized by further BM accrual of T cells with reduced Th1 and persistently increased Th2 cytokine production, which associated with accumulation of CD206Tie2 macrophages, and increased pro-angiogenic cytokines and microvessel density (MVD). Notably, MVD was also increased at diagnosis in the BM of MGUS and SMM patients that subsequently progressed to MM when compared with MGUS and SMM that remained quiescent. These findings suggest a multistep pathogenic process in MM, in which the immune system may contribute to angiogenesis and disease progression. They also suggest initiating a large multicenter study to investigate MVD in asymptomatic patients as prognostic factor for the progression and outcome of this disease.
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http://dx.doi.org/10.1080/2162402X.2015.1008850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485787PMC
June 2015

A pilot Phase I study combining peptide-based vaccination and NGR-hTNF vessel targeting therapy in metastatic melanoma.

Oncoimmunology 2014 Nov 21;3(11):e963406. Epub 2014 Dec 21.

Unit of Immuno-biotherapy of Melanoma and Solid Tumors; San Raffaele Foundation Research Institute ; Via Olgettina , Milan.

Administration of NGR-TNF, a tumor vessel-targeting and tumor necrosis factor α TNFα) peptide conjugate, with immunotherapy has been shown to inhibit tumor growth in mice. Thus, we planned a Phase I pilot clinical trial to assess safety, immune and clinical response of this combination treatment for advanced melanoma. NA17.A2 and MAGE-3.A1 peptides were used as vaccine. HLA-A*0201 or HLA-A*01 metastatic melanoma patients received human NGR-hTNF i.v. alternating with s.c. weekly injections of either of the peptides emulsified in Montanide. The T-cell response was assessed using peripheral blood mononuclear cells (PBMCs) before, during and after therapy. The serum level of chromogranin A (CgA), soluble TNF receptors (sTNFR1/2), vascular endothelial growth factor (VEGF), and MIP-1β and MCP-1 chemokines, was determined. In 3 subjects, pre- and post-treatment tumor lesions were examined by immunohistochemistry. Clinically, chills were observed in 4 patients during NGR-hTNF infusion and erythema at vaccination site was seen in 7 patients. T-cell response against the vaccine or against other melanoma-associated antigens was detectable after treatment in 6 out of 7 tested patients. Low level or reduction of CgA and sTNFR and increase of MIP-1β and MCP-1 were found in patients sera. In the lesions examined the immune infiltrate was scanty but macrophage number increased in post-therapy lesions. From a clinical standpoint, a long term survival (>4 months) was found in 6 out of 8 evaluable patients (4, 4, 7, 11, 23+, 25+, 25+, 29+ months). The combination of NGR-hTNF and vaccine in metastatic melanoma patients was well tolerated, often associated with an T cell response and long-term overall survival. These findings warrant confirmation in a larger group of patients.
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http://dx.doi.org/10.4161/21624011.2014.963406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368149PMC
November 2014

Tenascin-C Protects Cancer Stem-like Cells from Immune Surveillance by Arresting T-cell Activation.

Cancer Res 2015 May 25;75(10):2095-108. Epub 2015 Mar 25.

Division of Immunology, Transplantation and Infectious Diseases, Cellular Immunology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Precociously disseminated cancer cells may seed quiescent sites of future metastasis if they can protect themselves from immune surveillance. However, there is little knowledge about how such sites might be achieved. Here, we present evidence that prostate cancer stem-like cells (CSC) can be found in histopathologically negative prostate draining lymph nodes (PDLN) in mice harboring oncogene-driven prostate intraepithelial neoplasia (mPIN). PDLN-derived CSCs were phenotypically and functionally identical to CSC obtained from mPIN lesions, but distinct from CSCs obtained from frank prostate tumors. CSC derived from either PDLN or mPIN used the extracellular matrix protein Tenascin-C (TNC) to inhibit T-cell receptor-dependent T-cell activation, proliferation, and cytokine production. Mechanistically, TNC interacted with α5β1 integrin on the cell surface of T cells, inhibiting reorganization of the actin-based cytoskeleton therein required for proper T-cell activation. CSC from both PDLN and mPIN lesions also expressed CXCR4 and migrated in response to its ligand CXCL12, which was overexpressed in PDLN upon mPIN development. CXCR4 was critical for the development of PDLN-derived CSC, as in vivo administration of CXCR4 inhibitors prevented establishment in PDLN of an immunosuppressive microenvironment. Taken together, our work establishes a pivotal role for TNC in tuning the local immune response to establish equilibrium between disseminated nodal CSC and the immune system.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-2346DOI Listing
May 2015

Induction of T-cell memory by a dendritic cell vaccine: a computational model.

Bioinformatics 2014 Jul 6;30(13):1884-91. Epub 2014 Mar 6.

Department of Drug Science and Department of Mathematics and Computer Science, University of Catania, 95125 Catania, San Raffaele Scientific Institute and Università Vita Salute San Raffaele, 20132 Milan, Politecnico di Milano, 20133 Milano and San Raffaele Scientific Institute, 20132 Milan, Italy.

Motivation: Although results from phase III clinical trials substantially support the use of prophylactic and therapeutic vaccines against cancer, what has yet to be defined is how many and how frequent boosts are needed to sustain a long-lasting and protecting memory T-cell response against tumor antigens. Common experience is that such preclinical tests require the sacrifice of a relatively large number of animals, and are particularly time- and money-consuming.

Results: As a first step to overcome these hurdles, we have developed an ordinary differential equation model that includes all relevant entities (such as activated cytotoxic T lymphocytes and memory T cells), and investigated the induction of immunological memory in the context of wild-type mice injected with a dendritic cell-based vaccine. We have simulated the biological behavior both in the presence and in the absence of memory T cells. Comparing results of ex vivo and in silico experiments, we show that the model is able to envisage the expansion and persistence of antigen-specific memory T cells. The model might be applicable to more complex vaccination schedules and substantially in any biological condition of prime-boosting.

Availability And Implementation: The model is fully described in the article.
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http://dx.doi.org/10.1093/bioinformatics/btu059DOI Listing
July 2014