Safety and efficacy of preoperative chemotherapy for muscle-invasive bladder cancer in elderly patients.

PURPOSE: This study aimed at describing the feasibility and oncological outcomes of standard cisplatin-based neoadjuvant chemotherapy (C-NAC) for muscle-invasive bladder cancer (MIBC) in patients aged ≥ 75 and assess the impact of baseline geriatric parameters. METHODS: This retrospective study included patients with stage cT2-4NanyM0 MIBC aged 75 and older treated with ≥ 1 cycle of C-NAC from 2011 to 2021 at a high-volume academic center. Primary outcome was overall survival (OS). Secondary outcomes were chemotherapy feasibility (administration of ≥ 4 cycles), safety, and pathological downstaging. RESULTS: Fifty-six patients were included. Median age was 79 (range 75-90). C-NAC regimen was ddMVAC in 41 patients and GC in 15. Seventy-three percent of patients received ≥ 4 cycles of C-NAC. Grade ≥ 3 toxicity was observed in 55% of patients. The febrile neutropenia rate was 7%. Thirty patients underwent cystectomy, and 13 underwent chemoradiotherapy. Three-year OS was 63%. Geriatric parameters polypharmacy, undernutrition, and age-adjusted Charlson comorbidity index ≥ 8 predicted worse OS. CONCLUSION: Standard-of-care C-NAC and local treatments are feasible in selected elderly MIBC patients, with efficacy and safety findings similar to that observed in pivotal trials with younger patients. The prognostic impact of geriatric parameters underlines the need for specialized evaluation before treatment initiation.

Transcriptomic Profiling of Upper Tract Urothelial Carcinoma: Bladder Cancer Consensus Classification Relevance, Molecular Heterogeneity, and Differential Immune Signatures.

Analyses of large transcriptomics data sets of muscle-invasive bladder cancer (MIBC) have led to a consensus classification. Molecular subtypes of upper tract urothelial carcinomas (UTUCs) are less known. Our objective was to determine the relevance of the consensus classification in UTUCs by characterizing a novel cohort of surgically treated ≥pT1 tumors. Using immunohistochemistry (IHC), subtype markers GATA3-CK5/6-TUBB2B in multiplex, CK20, p16, Ki67, mismatch repair system proteins, and PD-L1 were evaluated. Heterogeneity was assessed morphologically and/or with subtype IHC. FGFR3 mutations were identified by pyrosequencing. We performed 3'RNA sequencing of each tumor, with multisampling in heterogeneous cases. Consensus classes, unsupervised groups, and microenvironment cell abundance were determined using gene expression. Most of the 66 patients were men (77.3%), with pT1 (n = 23, 34.8%) or pT2-4 stage UTUC (n = 43, 65.2%). FGFR3 mutations and mismatch repair-deficient status were identified in 40% and 4.7% of cases, respectively. Consensus subtypes robustly classified UTUCs and reflected intrinsic subgroups. All pT1 tumors were classified as luminal papillary (LumP). Combining our consensus classification results with those of previously published UTUC cohorts, LumP tumors represented 57.2% of ≥pT2 UTUCs, which was significantly higher than MIBCs. Ten patients (15.2%) harbored areas of distinct subtypes. Consensus classes were associated with FGFR3 mutations, stage, morphology, and IHC. The majority of LumP tumors were characterized by low immune infiltration and PD-L1 expression, in particular, if FGFR3 mutated. Our study shows that MIBC consensus classification robustly classified UTUCs and highlighted intratumoral molecular heterogeneity. The proportion of LumP was significantly higher in UTUCs than in MIBCs. Most LumP tumors showed low immune infiltration and PD-L1 expression and high proportion of FGFR3 mutations. These findings suggest differential response to novel therapies between patients with UTUC and those with MIBC.

Survival after sequential neoadjuvant chemotherapy followed by trimodal treatment or radical cystectomy for muscle-invasive bladder cancer.

PURPOSE: to assess the respective outcomes of patients with localized muscle-invasive bladder cancer (MIBC) treated by either radical cystectomy (RC) or trimodal treatment (TMT) depending on pathological response to previous neoadjuvant chemotherapy (NAC) assessed on cystectomy specimen or post-NAC transurethral resection (TURB) specimen, respectively. PATIENT AND METHODS: We retrospectively included all consecutive patients treated in one academic center with cisplatin-based NAC followed by RC or TMT for cT2-3N0M0 MIBC between 2014 and 2021. Primary endpoint was metastasis-free survival (MFS) in both treatment groups and according to pathological response to NAC. Local recurrence-free survival and conservative management failure (metastasis-free bladder-intact survival) for patients treated with TMT were assessed. RESULTS: 104 patients were included, 26 treated with TMT and 78 with RC. The rate of complete pathological response was 47.4% in patients treated with RC (ypT0) and 66.7% in patients treated with TMT (ycT0). Median follow-up was 34.9 months. Four-year MFS was 72% in both treatment groups. Four-year MFS was 85% in both ypT0 RC patients and ycT0 TMT patients. ycT0 stage was associated with low rates of intravesical recurrence and conservative management failure. CONCLUSION: Patients with post-NAC ycT0 stage treated with TMT have favorable oncological outcomes similar to those of ypT0 patients treated with RC. Assessment of complete histological response with TURB after NAC may help in selecting the best candidates for bladder preservation with TMT.

Clinical outcomes of adapted hypofractionated radiotherapy for bladder cancer in elderly patients.

OBJECTIVE: To investigate the feasibility, efficacy, and safety of trimodal therapy (TMT) using a bifractionated split-course hypofractionated radiotherapy (RT) for non-metastatic muscle-invasive bladder cancer (MIBC) in elderly patients. PATIENTS AND METHODS: We retrospectively reviewed the characteristics and outcomes of patients aged >75 years with non-metastatic MIBC suitable or not for radical cystectomy (RC) and treated with transurethral resection of bladder tumour followed by concomitant radio-chemotherapy (platinum salt and 5-fluorouracil) at two institutions (Saint Louis Hospital, Paris, France and European Georges Pompidou Hospital, Paris, France) between 1990 and 2021. RT consisted of an adapted bifractionated split-course hypofractionated RT. Acute toxicities were reported according to Common Terminology Criteria for Adverse Events version 5.0 and late toxicities were reported according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer late radiation morbidity scoring schema. The primary end-point was overall survival (OS). Secondary end-points included other survivals outcomes and safety. RESULTS: A total of 122 patients were identified, with a median (range) follow-up of 51.1 (0.5-210.8) months. In all, 83.5% of patients completed radio-chemotherapy. The OS rate was 61.7% at 3 years and 51.2% at 5 years. In multivariate analysis, the completion of RT and concomitant chemotherapy were significantly associated with better OS and cancer-specific survival. For patients fit for RC, a complete histological response was achieved for 77 patients (91.7%) with radio-chemotherapy and the bladder conservation rate was 90.5%. Acute and late Grade ≥3 toxicities were <5%. CONCLUSION: Bifractionated split-course hypofractionated RT with concomitant chemotherapy regimen appears to be well-tolerated and effective. Trimodal treatment seems to be a curative option for elderly patients unfit for radical surgery compared with palliative care and may contribute to improved survival in these patients.

BK virus genotypes and humoral response in kidney transplant recipients with BKV associated nephropathy.

BACKGROUND: Among kidney transplant recipients (KTR) with BK virus associated nephropathy (BKVN), BKV genotypes' evolution and anti-BKV humoral response are not well established. We aim to analyze BKV replication and genetic evolution following transplantation, and characterize concomitant anti-BKV-VP1 humoral response. METHODS: We retrospectively analyzed 32 cases of biopsy-proven BKVN. Stored plasma and kidney biopsies were tested for BKV viral load, and VP1 sequencing performed on positive samples. BKV-VP1 genotype-specific neutralizing antibodies (NAbs) titers were determined at transplantation and BKVN. RESULTS: At the time of BKVN diagnosis, BKV viral load was 8.2 log10 IU/106 cells and 5.4 log10 IU/mL in kidney and plasma, respectively. VP1 sequencing identified the same BKV-subtype in both compartments in 31/32 cases. At the time of transplantation, 8/20 (40%) of biopsies tested positive for BKV detection, whereas concomitant BKV viremia was negative. VP1 sequencing identified a different subtype compared to BKVN in 5/6 of these samples. This was confirmed following transplantation: 8 patients had a BKV+ biopsy before BKV viremia, and VP1 sequencing identified a different subtype compared to BKVN in all of them. After the onset of BKV viremia and prior to BKVN diagnosis, the BKV subtype in BKV+ plasma and kidney biopsy was the same as the one isolated at BKVN. BKV-VP1 NAbs titers were significantly higher at the time of BKVN compared to transplantation (p = .0031), with similar titers across genotypes. CONCLUSION: Altogether, our data suggest that among some KTR with BKVN, the BKV genotype from the donor may not be responsible for BKVN pathogenesis.

Safety Profile of Ambulatory Prostatic Artery Embolization after a Significant Learning Curve: Update on Adverse Events.

BACKGROUND: to report the safety of outpatient prostatic artery embolization (PAE) after a significant learning curve. METHODS: a retrospective bi-institutional study was conducted between June 2018 and April 2022 on 311 consecutive patients, with a mean age of 69 years ± 9.8 (47-102), treated by outpatient PAE. Indications included lower urinary tract symptoms, acute urinary retention, and hematuria. When needed, 3D-imaging and/or coil protection of extra-prostatic supplies were performed to avoid non-target embolization. Adverse events were monitored at 1-, 6-, and 12-month follow-ups. RESULTS: bilateral PAE was achieved in 305/311 (98.1%). Mean dose area product/fluoroscopy times were 16,408.3 ± 12,078.9 (2959-81,608) µGy.m2/36.3 ± 1.7 (11-97) minutes. Coil protection was performed on 67/311 (21.5%) patients in 78 vesical, penile, or rectal supplies. Embolization-related adverse events varied between 0 and 2.6%, access-site adverse events between 0 and 18%, and were all minor. There was no major event. CONCLUSION: outpatient PAE performed after achieving a significant learning curve may lead to a decreased and low rate of adverse events. Experience in arterial anatomy and coil protection may play a role in safety, but the necessity of the latter in some patterns may need confirmation by additional studies in randomized designs.

Methods for Establishing a Renal Cell Carcinoma Tumor Spheroid Model With Immune Infiltration for Immunotherapeutic Studies.

Tumor spheroids play an increasingly important role in cancer research. Their ability to recapitulate crucial features of tumor biology that are lost in the classically used 2D models along with their relative simplicity and handiness have made them the most studied 3D tumor model. Their application as a theranostic tool or as a means to study tumor-host interaction is now well-established in various cancers. However, their use in the field of Renal Cell Carcinoma (RCC) remains very limited. The aim of this work is to present methods to implement a basic RCC spheroid model. These methods cover the steps from RCC tumor dissociation to spheroid infiltration by immune cells. We present a protocol for RCC dissociation using Liberase TM and introduce a culture medium containing Epithelial Growth Factor and Hydrocortisone allowing for faster growth of RCC primary cells. We show that the liquid overlay technique allows for the formation of spheroids from cell lines and from primary cultures. We present a method using morphological criteria to select a homogeneous spheroid population based on a Fiji macro. We then show that spheroids can be infiltrated by PBMCs after activation with OKT3 or IL-15. Finally, we provide an example of application by implementing an immune spheroid killing assay allowing observing increased spheroid destruction after treatment with PD-1 inhibitors. Thus the straightforward methods presented here allow for efficient spheroid formation for a simple RCC 3D model that can be standardized and infused with immune cells to study immunotherapies.

Feasibility of Outpatient Transradial Prostatic Artery Embolization and Safety of a Shortened Deflation Protocol for Hemostasis.

BACKGROUND: to evaluate the safety and feasibility of a shorter time to hemostasis applied to outpatient transradial (TR) Prostatic Artery Embolization (PAE). METHODS: a retrospective bi-institutional study was conducted between July 2018 and April 2022 on 300 patients treated by outpatient TR PAE. Indications included lower urinary tract symptoms, acute urinary retention, and hematuria. Mean patient height was 176 ± 6.3 (158-192) cm. The primary endpoint was safety of a 45 min deflation protocol for hemostasis. The secondary endpoint was the feasibility of PAE using TR access. RESULTS: technical success was 98.7% (296/300). There was one failure due to patient height. Mean DAP/fluoroscopy times were 16,225 ± 12,126.3 (2959-81,608) µGy·m2/35 ± 14.7 (11-97) min, and mean time to discharge was 80 ± 6 (75-90) min. All access site and embolization-related adverse events were minor. Mild hematoma occurred in 10% (30/300), radial artery occlusion (RAO) in 10/300 (3.3%) cases, and history of smoking was a predictor for RAO. There was no major event. CONCLUSION: the safety of TR PAE using a 45 min time to hemostasis was confirmed, and TR PAE is feasible in most cases. Radial artery occlusion was still observed and may be favored by smoking.

The HLA-G immune checkpoint: a new immuno-stimulatory role for the α1-domain-deleted isoform.

The heterogeneity of cancer cells, in part maintained via the expression of multiple isoforms, introduces significant challenges in designing effective therapeutic approaches. In this regard, isoforms of the immune checkpoint HLA-G have been found in most of the tumors analyzed, such as ccRCC, the most common human renal malignancy. In particular, HLA-G∆α1, which is the only HLA-G isoform described that lacks the α1 extracellular domain, has been newly identified in ccRCC and now here in trophoblasts. Using a cellular model expressing HLA-G∆α1, we have uncovered its specific and overlapping functional roles, relative to the main HLA-G isoform, i.e., the full-length HLA-G1. We found that HLA-G∆α1 has several particular features: (i) although possessing the α3 domain, it does not associate with ß2-microglobulin; (ii) it may not present peptides to T cells due to absence of the peptide-binding groove; and (iii) it exerts immune-stimulatory activity towards peripheral blood NK and T cells, while all known isoforms of HLA-G are immune-inhibitory checkpoint molecules. Such immune-stimulatory properties of HLA-G∆α1 on the cytotoxic function of peripheral blood NK cells are individual dependent and are not exerted through the interaction with the known HLA-G receptor, ILT2. Importantly, we are faced here with a potential antitumor effect of an HLA-G isoform, opposed to the pro-tumor properties described for all other HLA-G isoforms, which should be taken into account in future therapeutic designs aimed at blocking this immune checkpoint.

Operative and Midterm Oncological Outcome of Focal Salvage Cryotherapy for Localized Prostate Cancer.

BACKGROUND: Local recurrence after radiation therapy for prostate cancer is a major clinical issue. Various local treatments are available with mitigated functional and oncological outcomes. The aim of the present study was to evaluate perioperative and oncological results of salvage cryotherapy (CT) as treatment of local recurrence of prostate cancer. METHODS: We retrospectively reviewed all patients treated with hemi-prostatic salvage CT for local recurrence of prostate cancer in 1 academic hospital between November 2011 and April 2019. Local recurrence was defined according to the Phoenix criteria (prostate-specific antigen [PSA] nadir + 2 ng/mL), associated with a prostatic MRI target lesion and confirmed by biopsy. Perioperative and functional complications were collected. Cox regression was conducted to assess factors associated with time to initiation of androgen deprivation therapy (ADT). Statistical analyses were conducted using R Studio. RESULTS: A total of 29 patients were treated with an average follow-up of 37.6 months. Median age at CT was 77 years. Median PSA before CT was 5.1 ng/mL (min-max: 2.74-18). 17.2% of patients displayed a high D'Amico risk group. Median hospital stay was 1.4 days. Four patients (13.8%) experienced postoperative acute urinary retention. Nineteen patients (65.5%) experienced late functional complications (3 erectile dysfunctions, 3 stress incontinence, and 13 urinary frequency). Fourteen patients displayed recurrence after salvage treatment (48.2%). Median time to introduction of ADT was 15.1 months. ADT-free survival at 1 and 2 years was, respectively, 74% and 61%. In multivariate analysis, ISUP score 4 and PSA nadir <1 ng/mL after CT were significantly associated with time to ADT initiation. CONCLUSIONS: Salvage focal CT may delay the use of ADT in locally recurrent prostate cancer after RT and offers an alternative for eligible patients. The technique was feasible with acceptable perioperative morbidity and acceptable midterm oncological outcome.

Perioperative outcomes of transurethral resection for t1 bladder tumors: quality evaluation based on patient, tumor and surgeon criteria.

INTRODUCTION: Transurethral resection of bladder tumor (TURBT) is a fundamental but challenging step in the diagnosis and treatment of non-muscle invasive bladder cancer (NMIBC). The first- and second-look TURBT are central in the management of T1 tumors. MATERIALS AND METHODS: We retrospectively reviewed all patients treated with TURBT for T1 urothelial cell carcinoma (UCC) of the bladder in one academic institution between 2007 and 2017. Quality of TURBT was evaluated based on the presence/absence of muscle on pathology report, the presence/absence of residual tumor on the second look and the occurrence of complications. Patient-, surgeon- and tumor-related factors were investigated for their association with TURBT quality. RESULTS: 283 patients were included. Second-look resection was performed after a mean delay of 54 days. Muscle was observed in 85.9% of the samples on the first TURBT. On the second-look resection, UCC was observed in 52.3% of the samples. 38 complications were reported after the first TURBT (13.4%). Surgeon's experience was the only factor significantly associated with occurrence of post-operative complications (OR = 0.40; p = 0.04). Location of the tumor at the bottom of the bladder was a risk factor for not finding muscle at pathological analysis (OR = 0.20; p = 0.06). Male gender, multiplicity and tumor located at the bottom of the bladder were significantly associated with residual disease on reTURBT. In multivariate analysis, only male gender (OR = 4.71; p = 0.02) and tumor multiplicity remained significant (OR for unique tumor = 0.36; p = 0.02). CONCLUSION: TURBT is a challenging procedure and surgeon's experience is crucial in reducing the rate of post-operative complications. Technical difficulties resulting from patient's gender, tumor location or number of tumors may be as important as oncological factors in deciding whether or not to perform a second-look resection.

Tumor infiltrating and peripheral CD4+ILT2+ T cells are a cytotoxic subset selectively inhibited by HLA-G in clear cell renal cell carcinoma patients.

HLA-G: ILT2 has recently been positioned as a major immune checkpoint in urologic cancers. In clear cell renal cell carcinoma (ccRCC), tumor-infiltrating CD8+ T cells expressing ILT2 are a highly cytotoxic cell population, distinct from PD1+ T cells, and whose function is inhibited by HLA-G+ targets. Here we report that ILT2 receptor can also be expressed by CD4+ T cells in urologic cancer patients. In the course of deciphering the role of these ILT2+CD4+ T cells, we found a statistical association between the tumor context and these T cells, and a positive correlation between the levels of peripheral and intra-tumoral CD4+ILT2+ T cells. Phenotypic analyses revealed that CD4+ILT2+ T cells express memory T cell (CD27-CD28-CD57+) and cytotoxicity (Tbet+Perforin+KLRG1+NKp80+GPR56+) markers, consistent with a CD4+CTL phenotype. Functional assays showed that ccRCC-infiltrating CD4+ILT2+ T cells indeed have high cytolytic properties and therefore function as proper CD4+CTLs, but are selectively inhibited by HLA-G+ targets. Clinical relevance was provided by immunohistochemical analyses on ccRCC tumor lesions with HLA-G+ HLA class II+ tumor cells next to CD4+ T cell infiltrates. Our findings provide evidence supporting that ILT2+ T cells constitute a reservoir of intratumor cytotoxic T cells that is not targeted by the current checkpoint inhibitors, but could be by anti-HLA-G/anti-ILT2 antibodies as novel immunotherapy in HLA-G+ tumors.

The immune-checkpoint HLA-G/ILT4 is involved in the regulation of VEGF expression in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC), the most aggressive renal cancer, is characterized by early lymph node metastases and bad prognosis. Most therapies targeting advanced or metastatic ccRCC are based, as first-line treatment, on the administration of the vascular endothelial growth factor (VEGF) neutralizing antibody termed Bevacizumab. Despite proven benefits, the expected results were not obtained for the majority of patients. The possibility that an intricate interplay between angiogenesis and immune-checkpoints might exist lead us to evaluate tumor angiogenesis, by means of VEGF expression together with the immune checkpoint HLA-G/ILT4. METHODS: Tumor specimens were obtained from patients from two separate cohorts: One from "Evita Pueblo" Hospital from Berazategui, (Buenos Aires, Argentina) and the second includes patients surgically operated at the Urology Department of Saint-Louis Hospital (Paris, France) with a confirmed ccRCC diagnosis. Immunohistochemistry was performed with specific antibodies directed against HLA-G, VEGF-A, VEGF-C, D240, CD34, ILT4 and Ca-IX. In addition, gene expression levels were measured in a cell line derived from a ccRCC patient by semi-quantitative RT-PCR. RESULTS: Our results show that the highly vascularized tumors of ccRCC patients express high levels of VEGF and the immune-checkpoint HLA-G. In addition, ILT4, one of the HLA-G receptors, was detected on macrophages surrounding tumor cells, suggesting the generation of an immune-tolerant microenvironment that might favor tumorigenesis. Notably, RT-qPCR analysis provided the first evidence on the transcriptional relationship between HLA-G/ILT4 and the VEGF family. Namely, in the presence of HLA-G or ILT4, the levels of VEGF-A are diminished whereas those of VEGF-C are increased. CONCLUSIONS: In an effort to find new therapeutic molecules and fight against metastasis dissemination associated with the poor survival rates of ccRCC patients, these findings provide the rationale for co-targeting angiogenesis and the immune checkpoint HLA-G.

Comprehensive landscape of immune-checkpoints uncovered in clear cell renal cell carcinoma reveals new and emerging therapeutic targets.

Clear cell renal cell carcinoma (ccRCC) constitutes the most common renal cell carcinoma subtype and has long been recognized as an immunogenic cancer. As such, significant attention has been directed toward optimizing immune-checkpoints (IC)-based therapies. Despite proven benefits, a substantial number of patients remain unresponsive to treatment, suggesting that yet unreported, immunosuppressive mechanisms coexist within tumors and their microenvironment. Here, we comprehensively analyzed and ranked forty-four immune-checkpoints expressed in ccRCC on the basis of in-depth analysis of RNAseq data collected from the TCGA database and advanced statistical methods designed to obtain the group of checkpoints that best discriminates tumor from healthy tissues. Immunohistochemistry and flow cytometry confirmed and enlarged the bioinformatics results. In particular, by using the recursive feature elimination method, we show that HLA-G, B7H3, PDL-1 and ILT2 are the most relevant genes that characterize ccRCC. Notably, ILT2 expression was detected for the first time on tumor cells. The levels of other ligand-receptor pairs such as CD70:CD27; 4-1BB:4-1BBL; CD40:CD40L; CD86:CTLA4; MHC-II:Lag3; CD200:CD200R; CD244:CD48 were also found highly expressed in tumors compared to adjacent non-tumor tissues. Collectively, our approach provides a comprehensible classification of forty-four IC expressed in ccRCC, some of which were never reported before to be co-expressed in ccRCC. In addition, the algorithms used allowed identifying the most relevant group that best discriminates tumor from healthy tissues. The data can potentially assist on the choice of valuable immune-therapy targets which hold potential for the development of more effective anti-tumor treatments.

Operative and oncological results and impact on treatment strategy of systematic renal tumor biopsy: Comparison between patients < and >75 years old.

BACKGROUND: Proper usage of renal tumor biopsy (RTB) remains to be determined in the setting of renal tumors diagnosis, particularly in the elderly population. The aim of the study was to evaluate the perioperative and pathological results of RTB in a population of patients over 75 and to compare the performance of the procedure to their younger counterparts. MATERIAL AND METHODS: Systematic RTB were prospectively performed in a single center between 2009 and 2012. Patients' and tumor characteristics, operative and pathological results were collected. Data were compared between patients under and over 75 years old. Particular attention was paid to influence of RTB on treatment decision-making. RESULTS: A total of 180 patients were included (137 patients <75 years and 43 > 75 years). Size of tumor, clinical stage, radiological aspect and RENAL score were not statistically different between patients under or over 75 years. No difference was observed between the 2 groups regarding complication rate (2.9% vs. 0%, respectively, P = 0.625). One hundred fifty-seven patients (87.2%) had a positive diagnosis at first RTB, with no difference between the 2 groups regarding histology (P = 0.942). After biopsy, only 73.1% of patients <75 years and 70.7% of patients >75 years had concordance between radiological and histological findings (P = 0.919). Treatment decision was challenged after RTB in 21.8% of patients <75 years and in 25.0% of patients >75 years. CONCLUSIONS: RTB was as safe and accurate in the eldest population, as it is in the general population, and should be performed routinely considering its influence on patient management strategy.

CD8+PD-1-ILT2+ T Cells Are an Intratumoral Cytotoxic Population Selectively Inhibited by the Immune-Checkpoint HLA-G.

Only some cancer patients respond to the immune-checkpoint inhibitors being used in the clinic, and other therapeutic targets are sought. Here, we investigated the HLA-G/ILT2 checkpoint in clear-cell renal-cell carcinoma (ccRCC) patients and focused on tumor-infiltrating CD8+ T lymphocytes (TIL) expressing the HLA-G receptor ILT2. Using transcriptomics and flow cytometry, we characterized both peripheral blood and tumor-infiltrating CD8+ILT2+ T cells from cancer patients as late-differentiated CD27-CD28-CD57+ cytotoxic effectors. We observed a clear dichotomy between CD8+ILT2+ and CD8+PD-1+ TIL subsets. These subsets, which were sometimes present at comparable frequencies in TIL populations, barely overlapped phenotypically and were distinguished by expression of exclusive sets of surface molecules that included checkpoint molecules and activating and inhibitory receptors. CD8+ILT2+ TILs displayed a more mature phenotype and higher expression of cytotoxic molecules. In ex vivo functional experiments with both peripheral blood T cells and TILs, CD8+ILT2+ T cells displayed significantly higher cytotoxicity and IFNγ production than their ILT2- (peripheral blood mononuclear cells, PBMC) and PD-1+ (TILs) counterparts. HLA-G expression by target cells specifically inhibited CD8+ILT2+ T-cell cytotoxicity, but not that of their CD8+ILT2- (PBMC) or CD8+PD-1+ (TIL) counterparts, an effect counteracted by blocking the HLA-G/ILT2 interaction. CD8+ILT2+ TILs may therefore constitute an untapped reservoir of fully differentiated cytotoxic T cells within the tumor microenvironment, independent of the PD1+ TILs targeted by immune therapies, and specifically inhibited by HLA-G. These results emphasize the potential of therapeutically targeting the HLA-G/ILT2 checkpoint in HLA-G+ tumors, either concomitantly with anti-PD-1/PD-L1 or in cases of nonresponsiveness to anti-PD-1/PD-L1.

[Lower urinary tract disorders in men: which management?] / Troubles du bas appareil urinaire chez l'homme : comment les traiter ?

Lower urinary tract disorders in men: which management? Initial management of men lower urinary tract symptoms is based on a well conducted interview and the realization of a frequency-volume chart. Dietary intervention associated with behavioral reeducation can be of great efficacy in combination with usual drug treatments. In case of failure, transuretral electrical resection of the prostate remains the reference, with possible emerging instrumental alternatives such as Urolift or prostatic embolization.

Troubles du bas appareil urinaire chez l'homme : comment les traiter ? La prise en charge initiale des troubles mictionnels de l'homme repose sur un entretien bien conduit et la réalisation d'un calendrier mictionnel. Des règles hygiénodiététiques associées à une rééducation comportementale peuvent rendre de grands services en association avec les traitements médicamenteux habituels. En cas d'échec, la résection endoscopique électrique de la prostate reste la référence, avec de possibles alternatives instrumentales émergentes comme le système Urolift ou l'embolisation prostatique.