Alessia Parodi | Università degli Studi di Genova (original) (raw)

Papers by Alessia Parodi

PLOS Pathogens, Apr 16, 2021

Journal of Experimental & Clinical Cancer Research

Background The combination of Programmed Cell Death 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4... more Background The combination of Programmed Cell Death 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) blockade has dramatically improved the overall survival rate for malignant melanoma. Immune checkpoint blockers (ICBs) limit the tumor’s immune escape yet only for approximately a third of all tumors and, in most cases, for a limited amount of time. Several approaches to overcome resistance to ICBs are being investigated among which the addition of epigenetic drugs that are expected to act on both immune and tumor cells. Guadecitabine, a dinucleotide prodrug of a decitabine linked via phosphodiester bond to a guanosine, showed promising results in the phase-1 clinical trial, NIBIT-M4 (NCT02608437). Methods We used the syngeneic B16F10 murine melanoma model to study the effects of immune checkpoint blocking antibodies against CTLA-4 and PD-1 in combination, with and without the addition of Guadecitabine. We comprehensively characterized the tumor’s and the host’s responses under...

Background: The combination of Programmed Cell Death 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen ... more Background: The combination of Programmed Cell Death 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) blockade has dramatically improved the overall survival rate for malignant melanoma. Immune checkpoint blockers (ICBs) limit the tumor’s immune escape yet only for approximately a third of all tumors and, in most cases, for a limited amount of time. Several approaches to overcome resistance to ICBs are being investigated among which the addition of epigenetic drugs that are expected to act on both immune and tumor cells. Guadecitabine, a dinucleotide prodrug of a decitabine linked via phosphodiester bond to a guanosine, showed promising results in the phase-1 clinical trial, NIBIT-M4 (NCT02608437). Methods: We used the syngeneic B16F10 murine melanoma model to study the effects of immune checkpoint blocking antibodies against CTLA-4 and PD-1 in combination, with and without the addition of Guadecitabine. We comprehensively characterized the tumor’s and the host’s responses und...

ABSTRACTCoronavirus disease 2019 (COVID-19) is characterized by a high heterogeneity of clinical ... more ABSTRACTCoronavirus disease 2019 (COVID-19) is characterized by a high heterogeneity of clinical presentation and outcomes. This is also true for patients undergoing maintenance hemodialysis (HD), who, due to specific clinical factors and immune status, represent a distinct subgroup of COVID-19 patients.Starting from this observation in this research letter we tested and validated in two cohorts of HD patients with COVID-19 (derivation and validation cohort, respectively) an innovative model which combines linear mixed effect modeling and cluster analysis on longitudinal.This study aimed to describe a methodology allowing patient stratification from simple and widely available data.Our results could be interesting not only to improve COVID-19 management but also to support the application of longitudinal cluster analysis strategy in other clinical settings.

Patients with severe SARS-CoV-2 infection have an overwhelming inflammatory response characterize... more Patients with severe SARS-CoV-2 infection have an overwhelming inflammatory response characterized by remarkable organs monocyte infiltration. We performed an immunophenotypic analysis on circulating monocytes in 19 COVID-19 patients in comparison with 11 naïve HIV-1 patients and 10 healthy subjects. Reduced frequency of classical monocytes and increased frequency of intermediate monocytes characterized COVID-19 patients with respect to both HIV naïve patients and healthy subjects. Intensity of C-C motif chemokine receptor 2 (CCR2) monocyte expression highly correlated with parameters of kidney dysfunction. Our data indicate that highly activated monocytes of COVID-19 patients may be pathogenically associated to the development of renal disease.

Journal of preventive medicine and hygiene, 2011

INTRODUCTION We previously reported that in HIV-1 infected patients circulating Vdelta1 T lymphoc... more INTRODUCTION We previously reported that in HIV-1 infected patients circulating Vdelta1 T lymphocytes (Vdelta1) increase and proliferate in vitro in response to Candida albicans (Ca). Herein, we analysed the effects of MF59 adjuvant on the Vdelta1 T cell responses to hemagglutinin (HA) and Ca in HIV-1 seropositive and seronegative adults after influenzal vaccine, to clarify th molecular mechanisms triggered in vivo by an adjuvanted vaccine against influenza virus. MATERIALS AND METHODS 58 seropositive (HIV-1+) and 48 seronegative (HIV-1-) subjects received influenzal vaccines containing or not the MF59 adjuvant. The follow-up of in vitro T cell proliferation and cytokine production (IL-17A, IL-22, IL-23, IL-6) to HA and Ca antigens were performed at different time points (at basal time and after 30 and 90 days from vaccination) by cytofluorimetric approaches. RESULTS We confirmed that in HIV-1 infected individuals the Vdelta1 T cell subset is expanded in HIV-1 infected individuals a...

Cancer Immunology, Immunotherapy, 2021

Debate is around the optimal immunization regimen for cancer vaccines since too intense vaccinati... more Debate is around the optimal immunization regimen for cancer vaccines since too intense vaccination schedules may exhaust reactive lymphocytes. GX301 is a telomerase-based cancer vaccine whose safety and immunological effects were tested in a phase I trial applying an eight administrations schedule. Main objective of this study was to comparatively analyse safety and immunological response to three GX301 regimens in metastatic castration-resistant prostate cancer patients with response/disease stability after docetaxel chemotherapy. This was a multicentre, randomized, parallel-group, open-label trial registered with EudraCT (2014-000095-26) and ClinicalTrials.gov (NCT02293707, 2014). Ninety-eight patients were randomized to receive either eight (regimen 1), four (regimen 2) or two (regimen 3) vaccine administrations. Sixty-three patients were assessable for the primary immunological end-point. Vaccine-specific immune responses were evaluated by intracellular staining for IFN, elispo...

Cancers, 2021

Head and neck squamous cell carcinoma (HNSCC) has a poor clinical outcome despite the presence of... more Head and neck squamous cell carcinoma (HNSCC) has a poor clinical outcome despite the presence of a rich CD8+ T cell tumor infiltrate in the majority of patients. This may be due to alterations of tumor infiltrating CD8+ T cells. Here, we performed a characterization of HNSCC infiltrating CD8+ T cells in a cohort of 30 patients. The results showed that differential intratumoral frequency of CD8+CD28+ T cells, CD8+CD28− T cells, and CD8+CD28−CD127−CD39+ Treg distinguished between HNSCC patients who did or did not respond to treatment. Moreover, high PD1 expression identified a CD8+CD28− T cell subpopulation, phenotypically/functionally corresponding to CD8+CD28−CD127−CD39+ Treg, which showed a high expression of markers of exhaustion. This observation suggests that development of exhaustion and acquisition of regulatory properties may configure the late differentiation stage for intratumoral effector T cells, a phenomenon we define as effector-to-regulatory T cell transition.

HIV-associated immunodeficiency is related to loss of CD4+ T cells. This mechanism does not expla... more HIV-associated immunodeficiency is related to loss of CD4+ T cells. This mechanism does not explain certain manifestations of HIV disease such as immunodeficiency events in patients with >500 CD4+ T cells/ml or occurrence of non-AIDS tumors. Hence, it is possible that other pathogenic mechanisms causing immunodeficiency may be at play during HIV infection. Little is known about the role of regulatory T CD4+ cells (Treg) in HIV immunodeficiency pathogenesis and studies on CD4+ Treg in HIV infected patients led to controversial results (1). Interestingly, similarities in composition and function of Treg subsets between tumors and HIV infection have been highlighted (2). The regulatory T cell compartment includes cells belonging to the CD8+ T cell lineage (3). Among the various CD8+ Treg subsets, a subgroup characterized by the CD8+CD28-CD127loCD39+ phenotype has been found to be highly concentrated within the tumor microenvironment (4). By polychromatic flow cytometry we show that HIVinfected patients have elevated circulating levels of functional CD8+CD28-CD127lowCD39+ T regulatory cells. These cells have antigen specificity against HIV proteins, suggesting their origin from HIV-specific T lymphocytes. Their frequency post \u1c0 anti-retroviral therapy (ART) correlates with HIV viremia, CD4+ T cell count and immune activation markers, suggesting their pathogenic involvement in AIDS- or non-AIDS related complications. Their increase after initiation of ART heralds a lack of virological or clinical response: hence their monitoring is clinically relevant

AIDS, 2014

This is a cross-sectional, case-control study analyzing the effect of antiretroviral therapy (ART... more This is a cross-sectional, case-control study analyzing the effect of antiretroviral therapy (ART) including or not maraviroc, on circulating monocytes and natural killer cells. Sixty-eight HIV-positive patients virologically suppressed receiving ART at least 6 months were subdivided as receiving (group 1) or not (group 2) maraviroc in their ART. Frequency of monocytes and natural killer cells, as well as their activation markers, were studied. Modulation of innate immune cells may be differently affected by combined ART.

BackgroundImmunocompromised patients show prolonged shedding of SARS-CoV-2 in nasopharyngeal swab... more BackgroundImmunocompromised patients show prolonged shedding of SARS-CoV-2 in nasopharyngeal swabs. We report a case of a prolonged persistence of viable SARS-CoV-2 associated with clinical relapses of COVID-19 in a lymphoma patient.MethodsNasopharyngeal swabs and blood samples were tested for SARS-CoV-2 by Real time-PCR (RT-PCR). On five positive nasopharyngeal swabs, we performed viral culture and next generation sequencing. We analysed the patients’ adaptive and innate immunity to characterize T and NK cell subsets.FindingsSARS-CoV-2 RT-PCR on nasopharyngeal swabs samples remained positive with cycle threshold mean values of 22 ± 1·3 for over 8 months. All five performed viral cultures were positive and genomic analysis confirmed a persistent infection with the same strain. Viremia resulted positive in three out of four COVID-19 clinical relapses and cleared each time after remdesivir treatment. T and NK cells dynamic was different in aviremic and viremic samples and no SARS-CoV-...

Blood

Background. Cord blood transplants (CBT) are associated with delayed or failed engraftment in a s... more Background. Cord blood transplants (CBT) are associated with delayed or failed engraftment in a significant proportion of patients (pts). Two of our previous observations suggested (i) that, in the animal model, direct intra-bone (i.b.) injection improves seeding efficiency and (ii) that the delayed engraftment was not related to an insufficient number of hematopoietic stem cells but rather to some difficulties to differentiate and maturate. Methods. Unrelated CB cells were selected for 29 consecutive pts (18 CB units were 4/6 HLA antigen matched, 10 were 5/6 and one 3/6 antigen matched). Median cell dose infused was 2.3 x10^7/kg (range 1.4 – 4.2). CB cells were concentrated in 4 syringes of 5 ml each and injected in the supero-posterior iliac crest (SPIC) under rapid general anesthesia (10 min. with propofol). Pts’ median age was 38 years (18–63); 25 had acute leukaemia (21 with refractory or relapsed disease and 4 high risk first remission leukemia); 2 chronic myeloid leukemia in ...

Brain, behavior, and immunity, 2018

White matter (WM) microstructural abnormalities and, independently, signs of immunological activa... more White matter (WM) microstructural abnormalities and, independently, signs of immunological activation were consistently demonstrated in bipolar disorder (BD). However, the relationship between WM and immunological alterations as well as their occurrence in the various phases of BD remain unclear. In 60 type I BD patients - 20 in manic, 20 in depressive, 20 in euthymic phases - and 20 controls we investigated: (i) diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) using a tract-based spatial statistics (TBSS) approach; (ii) circulating T cell subpopulations frequencies, as well as plasma levels of different cytokines; (iii) potential relationships between WM and immunological data. We found: (i) a significant widespread combined FA-RD alteration mainly in mania, with involvement of the body of corpus callosum (BCC) and superior corona radiata (SCR); (ii) significant increase in CD4+ T cells as well as significant decr...

Scientific Reports

Dendritic Cells (DCs) recognize infectious non-self molecules and engage the adaptive immune syst... more Dendritic Cells (DCs) recognize infectious non-self molecules and engage the adaptive immune system thereby initiating long lasting, antigen-specific responses. As such, the ability to activate DCs is considered a key tool to enhance the efficacy and quality of vaccination. Here we report a novel immunomodulatory sulfolipid named β-SQDG18 that prototypes a class of natural-derived glycolipids able to prime human DCs by a TLR2/TLR4-independent mechanism and trigger an efficient immune response in vivo. β-SQDG18 induces maturation of DC with the upregulation of MHC II molecules and co-stimulatory proteins (CD83, CD86), as well as pro-inflammatory cytokines (IL-12 and INF-γ). Mice immunized with OVA associated to β-SQDG18 (1:500) produced a titer of anti-OVA Ig comparable to traditional adjuvants. In an experimental model of melanoma, vaccination of C57BL/6 mice with β-SQDG18-adjuvanted hgp10 peptide elicited a protective response with a reduction in tumour growth and increase in survival.

Frontiers in Immunology, 2017

Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis, vasculo... more Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis, vasculopathy, and autoimmunity. Although the exact pathogenetic mechanisms behind SSc remain to be fully elucidated, a great deal of evidence suggests the existence of an unbalanced ratio between the effector and regulatory arms of the immune system. With regard to the T regulatory (Treg) compartment, we observed that CD8+ Treg subsets display functional defects in SSc-affected patients. Since CD127 down-modulation and CD39 upregulation have been observed on Treg subsets, the phenotypic expression of these molecules was analyzed on the CD8+CD28− Treg precursors and on CD8+ Treg cells generated in vitro through interleukin-10 commitment. Immunophenotypic data from SSc patients were compared to those obtained from healthy subjects. The analyses performed on ex vivo-isolated CD8+CD28− Treg precursors did not show any significant differences in CD39 or CD127 expression as compared to values obtained from healthy donors. On the contrary, in vitro-generated CD8+ Tregs obtained from SSc patients displayed reduced expression of the CD39 molecule as compared to controls. Moreover, the percentage of CD127+ cells was significantly higher in in vitro-generated CD8+ Tregs from SSc patients compared to CD8+ Tregs obtained from healthy donors. Taken together, these findings may indicate an impairment of maturation processes affecting CD8+ Treg cells in SSc patients. This impairment of maturation involves phenotypic alterations that are mainly characterized by a deficient CD39 upregulation and a lack of down-modulation of the CD127 molecule.

Oncotarget, 2016

AIRE is involved in susceptibility to melanoma perhaps regulating T cell immunity against melanom... more AIRE is involved in susceptibility to melanoma perhaps regulating T cell immunity against melanoma antigens (MA). To address this issue, AIRE and MAGEB2 expressions were measured by real time PCR in medullary thymic epithelial cells (mTECs) from two strains of C57BL/6 mice bearing either T or C allelic variant of the rs1800522 AIRE SNP. Moreover, the extent of apoptosis induced by mTECs in MAGEB2-specific T cells and the susceptibility to in vivo melanoma B16F10 cell challenge were compared in the two mouse strains. The C allelic variant, protective in humans against melanoma, induced lower AIRE and MAGEB2 expression in C57BL/6 mouse mTECs than the T allele. Moreover, mTECs expressing the C allelic variant induced lower extent of apoptosis in MAGEB2-specific syngeneic T cells than mTECs bearing the T allelic variant (p < 0.05). Vaccination against MAGEB2 induced higher frequency of MAGEB2-specific CTL and exerted higher protective effect against melanoma development in mice bearing the CC AIRE genotype than in those bearing the TT one (p < 0.05). These findings show that allelic variants of one AIRE SNP may differentially shape the MA-specific T cell repertoire potentially influencing susceptibility to melanoma.

PLOS ONE, 2016

The uremic toxin Indoxyl-3-sulphate (IS), a ligand of Aryl hydrocarbon Receptor (AhR), raises in ... more The uremic toxin Indoxyl-3-sulphate (IS), a ligand of Aryl hydrocarbon Receptor (AhR), raises in blood during early renal dysfunction as a consequence of tubular damage, which may be present even when eGFR is normal or only moderately reduced, and promotes cardiovascular damage and monocyte-macrophage activation. We previously found that patients with abdominal aortic aneurysms (AAAs) have higher CD14 + CD16 + monocyte frequency and prevalence of moderate chronic kidney disease (CKD) than age-matched control subjects. Here we aimed to evaluate the IS levels in plasma from AAA patients and to investigate in vitro the effects of IS concentrations corresponding to mild-to-moderate CKD on monocyte polarization and macrophage differentiation. Methods Free IS plasma levels, monocyte subsets and laboratory parameters were evaluated on blood from AAA patients and eGFR-matched controls. THP-1 monocytes, treated with IS 1, 10, 20 μM were evaluated for CD163 expression, AhR signaling and then induced to differentiate into macrophages by PMA. Their phenotype was evaluated both at the stage of semi-differentiated and fully differentiated macrophages. AAA and control sera were similarly used to treat THP-1 monocytes and the resulting macrophage phenotype was analyzed. Results IS plasma concentration correlated positively with CD14 + CD16 + monocytes and was increased in AAA patients. In THP-1 cells, IS promoted CD163 expression and transition to PLOS ONE |

Oncotarget, Jan 25, 2016

Bladder cancer has an unexplained, high recurrence rate. Causes of recurrence might include the p... more Bladder cancer has an unexplained, high recurrence rate. Causes of recurrence might include the presence of sporadic tumor micro-foci in the residual urothelial tissue after surgery associated with an inverted ratio between intratumoral effector and regulatory T cell subsets. Hence, surgical specimens of both tumors and autologous, macroscopically/histologically free-of-tumor tissues were collected from 28 and 20 patients affected by bladder or renal cancer, respectively. The frequencies of effector (IFNγ+ and IL17+ T cells) and regulatory (CD4+CD25hiCD127lo and CD8+CD28-CD127loCD39+ Treg) T cell subpopulations among tumor infiltrating lymphocytes were analyzed by immunofluorescence, while the gene expression of MAGE-A1 and MAGE-A2 tumor-associated antigens was studied by RT-PCR. The results show that both the T cell infiltrate and the frequency of MAGE-A1/A2 gene expression were comparable in tumors and in autologous free-of-tumor tissues in bladder cancer, while the autologous fre...

Cell Cycle, Jul 1, 2007

Rho family GTPases play important roles in the regulation of intracellular signals induced by act... more Rho family GTPases play important roles in the regulation of intracellular signals induced by activated heterotrimeric G proteins of the α 12/13 family. The α 12/13 subunits activate Rho GTPases through direct binding to a group of Rho guanine nucleotide exchange factors (GEFs) characterized by the presence of a G protein signaling-like (RGL) domain. The Rho GEF proto-Dbl, that does not contain a RGL domain, was also found to link Gα 12/13 signals to Rho. We have explored the effects of activated Gα 13 and Gα 13-associated G protein-coupled receptor (GPCR) agonists on proto-Dbl regulation. We show that activated Gα 13 , but not Gα 12 or Gα q , induces translocation of proto-Dbl to the cell membrane with consequent enlargement of cell body and membrane ruffling. These effects were evident also when Gα 13-associated GPCR agonists were used on cells expressing proto-Dbl and were accompanied by the activation of Cdc42 and RhoA GTPases and further downstream effector JNK and p38 kinases. Moreover, we show that both activated Gα 13 and GPCR agonists stimulate proto-Dbl interaction with ezrin to promote ezrin translocation to the plasma membrane. These results suggest a mechanism by which proto-Dbl and its effector pathways are regulated by Gα 13-mediated signals through association with ezrin.