[Show abstract][Hide abstract] ABSTRACT: Stage III melanomas (MM) require adequate adjuvant immunotherapy to prevent relapses. Prognostic factors are awaited to optimize the clinical management of these patients. The magnitude of metastatic lymph node (mLN) invasion and the BRAFV600 activating mutation have a clinical significance. Based on a comprehensive immunophenotyping of 252 parameters per patient in paired blood and mLN performed in 39 MM, we found that blood markers were as contributive as tumor-associated (TIL) immunotypes, and parameters associated with lymphocyte exhaustion/suppression showed higher clinical significance than those related to activation or lineage. High frequency of CD45RA+ CD4+ and CD3-CD56- TILs appear to be independent prognostic factors of short relapse-free survival. High NKG2D expression on CD8+TILs, low level of Treg TILs and low PD-L1 expression on circulating T cells were retained in the multivariate Cox analysis model to predict prolonged overall survival. Prospective studies must determine whether such immunological markers may guide adjuvant therapies in stage III MM.
Preview · Article · Jan 2016 · Journal of Investigative Dermatology
[Show abstract][Hide abstract] ABSTRACT: Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer. We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1−/− mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and as a result could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Gemcitabine is a chemotherapeutic agent frequently used by for the treatment of several malignancies both in the adjuvant and metastatic setting. Although myelosuppression is the most adverse event of this therapy, gemcitabine might induce severe pulmonary toxicities. We describe a case of pulmonary veno-occlusive disease (PVOD) related to gemcitabine.
The patient was an 83-year-old man with a metastatic pancreatic cancer who was treated by gemcitabine as first-line therapy. He was in good health and received no other chemotherapy. A dose of 1000 mg/m(2) of gemcitabine was administered over a 30-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. After a period of 6 months, a complete response was observed. Nevertheless, the patient developed a severe dyspnea, with arterial hypoxemia and very low lung diffusion for carbon monoxide. A CT scan showed diffuse ground glass opacities with septal lines, bilateral pleural effusion, and lymph node enlargement. On echocardiography, there was a suspicion of pulmonary hypertension with elevated systolic pulmonary artery pressure and normal left ventricular pressures. Right heart catheterization confirmed pulmonary hypertension and normal pulmonary artery occlusion pressure. Diagnosis of PVOD was made, and a gemcitabine-induced toxicity was suspected. A symptomatic treatment was started. At last follow-up, patient was in functional class I with near-normal of CT scan, arterial blood gases, and echocardiography. A gemcitabine-induced PVOD is the more likely diagnosis.
[Show abstract][Hide abstract] ABSTRACT: The development of inhibitors blocking STAT3 transcriptional activity is a promising therapeutic approach against cancer and inflammatory diseases. In this context, the selectivity of inhibitors against the STAT1 transcription factor is crucial as STAT3 and STAT1 play opposite roles in the apoptosis of tumor cells and polarization of the immune response. A structure-based virtual screening followed by a luciferase-containing promoter assay on STAT3 and STAT1 signaling were used to identify a selective STAT3 inhibitor. An important role of the aminotetrazole group in modulating STAT3 and STAT1 inhibitory activities has been established. Optimization of the hit compound leads to 23. This compound inhibits growth and survival of cells with STAT3 signaling pathway while displaying a minimal effect on STAT1 signaling. Moreover, it prevents lymphocyte T polarization into Th17 and Treg without affecting their differentiation into Th1 lymphocyte.
Full-text · Article · Sep 2015 · European Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Carbon nanotubes (CNTs) represent a class of nanomaterials with important potential for biomedical and biotechnological applications. CNT based vectorization is an emerging approach to the transport of nucleic acid through cell membrane but limited by detachment of DNA and degradation process. To increase DNA internalization, it was proved that cationic functionalized CNT was essential. In such a way, protamine efficiently used in several transfection processes is a cationic protein which was never associated to CNT. We propose here a novel nanovector based on single-walled carbon nanotubes (SWCNT) functionalized by protamine. Our results based on qPCR methods clearly indicate that protamine-SWCNT/DNA hybrids were much more successful than ammonium-SWCNT/DNA hybrids to cross cell membrane and penetrate into cells. We also studied the cellular internalization mechanism of our complexes and showed that endocytosis was strongly involved. Finally, we proposed molecular dynamic simulations to understand the formation of the protamine-SWCNT/DNA complex and to extract the interaction responsible for its deliverance upon cell membrane.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND Rectal linitis plastica (RLP) is a rare disease with poor outcome. It is often accompanied by a delayed histopathological diagnosis, primarily due to submucosal disease. A concentric ring pattern or "target sign" on T2-weighted magnetic resonance imaging (MRI) has been proposed as being characteristic for early suspicion. Even though RLP is more aggressive and has poorer survival than other rectal adenocarcinomas, no specific treatment is recommended. In this case report of 3 patients, we challenge the sensitivity of the characteristic radiological pattern, and we review the existing data for a treatment strategy. CASE REPORT One patient presented classic clinical characteristics of RLP with young age and advanced stage at diagnosis, with chemo-refractory disease and rapid fatal evolution. Biopsies confirmed the RLP with the presence of signet-ring cells (SRC) in a strong desmoplastic stromal reaction. However, the characteristic concentric ring pattern was absent. Instead, he had a large vegetative lesion with important tumor infiltration in mesorectum and pelvic organs, with major lymph node involvement. The 2 other patients presented resectable locally advanced disease with characteristic concentric ring pattern. No clinical and radiological responses were observed to neo-adjuvant chemoradiotherapy (CRT), including 1 patient with non-resectable disease at surgery and another with upstaged disease at pathological specimen after resection. However, data suggest 2 types of RLP: about half of patients are extremely sensitive to CRT with pathological complete response, and the other half are highly resistant with no response to CRT. Current data are insufficient to distinguish between these 2 populations. CONCLUSIONS The absence of a concentric ring pattern should not eliminate the suspicion of RLP, especially in young patients with aggressive clinical presentation. There are probably 2 types of RLP in terms of chemoradiosensitivity, and neoadjuvant CRT could delay the curative-intent surgery in refractory patients. Future molecular analysis of the tumor and its environment are required to characterize the 2 different forms of RLP to develop more personalized treatment strategies.
Full-text · Article · Aug 2015 · American Journal of Case Reports
[Show abstract][Hide abstract] ABSTRACT: Nowadays, immunotherapy represents one promising approach for cancer treatment. Recently, spectacular results of cancer immunotherapy clinical trials have confirmed the crucial role of immune system in cancer regression. Therapeutic cancer vaccine represents one widely used immunotherapy strategy to stimulate tumor specific T cell responses but clinical impact remains disappointing in targeting CD8 T cells. Although CD8 T cells have been initially considered to be the main protagonists, it is now clear that CD4 T cells also play a critical role in antitumor response. In this article, we discuss the role of tumor antigen-specific CD4 T cell responses and how we can target these cells to improve cancer vaccines.
[Show abstract][Hide abstract] ABSTRACT: The benefit of preoperative chemotherapy in resectable gastroesophageal adenocarcinomas was not observed in signet ring cell subtype. However, the potential interest of taxane-based preoperative chemotherapy on this subtype is still an unresolved issue. Nineteen patients with localized signet ring cell adenocarcinomas received taxane-based regimens, and 17 patients underwent surgery. Complete resection was achieved in 80 %, and median overall survival was 40.8 months (95 % confidence interval (CI), 20.2—not reached). Even though one patient achieved a complete pathological response, seven patients had an upstaging of their tumors at surgery. The potential benefits of taxane-based chemotherapy seem to be limited to a reduced number of patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-015-0148-y) contains supplementary material, which is available to authorized users.
Full-text · Article · May 2015 · Journal of Hematology & Oncology
[Show abstract][Hide abstract] ABSTRACT: Here, we report and investigate the genomic alterations of two novel cases of Non-Hodgkin Lymphoma (NHL) in children with Williams-Beuren syndrome (WBS), a multisystem disorder caused by 7q11.23 hemizygous deletion. Additionally, we report the case of a child with NHL and a somatic 7q11.23 deletion. Although the WBS critical region has not yet been identified as a susceptibility locus in NHL, it harbors a number of genes involved in DNA repair. The high proportion of pediatric NHL reported in WBS is intriguing. Therefore, the role of haploinsufficiency of genes located at 7q11.23 in lymphomagenesis deserves to be investigated.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-014-0082-4) contains supplementary material, which is available to authorized users.
Full-text · Article · Nov 2014 · Journal of Hematology & Oncology
[Show abstract][Hide abstract] ABSTRACT: Cancer-specific splice variants gain significant interest as they generate neo-antigens that could be targeted by immune cells. CD20, a membrane antigen broadly expressed in mature B cells and in B cell lymphomas, is subject to an alternative splicing named D393-CD20 leading to loss of membrane expression of the spliced isoform. D393-CD20 expression is detectable in transformed B cells and upregulated in various lymphoma B cells. In this study, we show that D393-CD20 is translated in malignant B cells and that D393-CD20 specific CD4 T cells producing IFN-γ are present in B-cell lymphoma patients. Then we have investigated whether the 20mer D393-CD20 peptide spanning the splicing site might be targeted by the immune system and we have shown that D393-CD20-specific CD4 Th1 clones could directly recognize malignant B cell lines and kill autologous lymphoma B cells indicating that D393-CD20-derived epitopes are naturally processed and presented on tumor cells. Finally, D393-CD20 peptide-based vaccination induced specific CD8 and CD4 T cell responses in HLA-humanized transgenic mice suggesting the presentation of D393-CD20 derived peptides on both HLA class-I and -II. These findings support further investigations on the potential use of D393-CD20 directed specific immunotherapy in B cell malignancies. This article is protected by copyright. All rights reserved.
Full-text · Article · Nov 2014 · International Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Here, we report and investigate the genomic alterations of two novel cases of Non-Hodgkin¿s Lymphoma (NHL) in children with Williams-Beuren syndrome (WBS), a multisystem disorder caused by 7q11.23 hemizygous deletion. Additionally, we report the case of a child with NHL and a somatic 7q11.23 deletion. Although the WBS critical region has not yet been identified as a susceptibility locus in NHL, it harbors a number of genes involved in DNA repair. The high proportion of pediatric NHL reported in WBS is intriguing. Therefore, the role of haploinsufficiency of genes located at 7q11.23 in lymphomagenesis deserves to be investigated.
[Show abstract][Hide abstract] ABSTRACT: Background
There are several reports demonstrating the role of CD8 T cells against Leishmania species. Therefore peptide vaccine might represent an effective approach to control the infection. We developed a rational polytope-DNA construct encoding immunogenic HLA-A2 restricted peptides and validated the processing and presentation of encoded epitopes in a preclinical mouse model humanized for the MHC-class-I and II.
Methods and Findings
HLA-A*0201 restricted epitopes from LPG-3, LmSTI-1, CPB and CPC along with H-2Kd restricted peptides, were lined-up together as a polytope string in a DNA construct. Polytope string was rationally designed by harnessing advantages of ubiquitin, spacers and HLA-DR restricted Th1 epitope. Endotoxin free pcDNA plasmid expressing the polytope was inoculated into humanized HLA-DRB1*0101/HLA-A*0201 transgenic mice intramuscularly 4 days after Cardiotoxin priming followed by 2 boosters at one week interval. Mice were sacrificed 10 days after the last booster, and splenocytes were subjected to ex-vivo and in-vitro evaluation of specific IFN-γ production and in-vitro cytotoxicity against individual peptides by ELISpot and standard chromium-51(51Cr) release assay respectively. 4 H-2Kd and 5 HLA-A*0201 restricted peptides were able to induce specific CD8 T cell responses in BALB/C and HLA-A2/DR1 mice respectively. IFN-γ and cytolytic activity together discriminated LPG-3-P1 as dominant, LmSTI-1-P3 and LmSTI-1-P6 as subdominant with both cytolytic activity and IFN-γ production, LmSTI-1-P4 and LPG-3-P5 as subdominant with only IFN-γ production potential.
Here we described a new DNA-polytope construct for Leishmania vaccination encompassing immunogenic HLA-A2 restricted peptides. Immunogenicity evaluation in HLA-transgenic model confirmed CD8 T cell induction with expected affinities and avidities showing almost efficient processing and presentation of the peptides in relevant preclinical model. Further evaluation will determine the efficacy of this polytope construct protecting against infectious challenge of Leishmania. Fortunately HLA transgenic mice are promising preclinical models helping to speed up immunogenicity analysis in a human related mouse model.