There is great need for vaccines against tuberculosis (TB) more efficacious than the licensed BCG. Our goal was to identify new vaccine benchmarks by identifying immune responses that distinguish individuals able to eradicate the infection (TB-resisters) from individuals with latent infection (LTBI-participants). TB-resisters had higher frequencies of circulating CD8+ glucose monomycolate (GMM)+ Granzyme-B+ T cells than LTBI-participants and higher proportions of polyfunctional conventional and nonconventional T cells expressing Granzyme-B and/or PD-1 after ex vivo M. tuberculosis stimulation of blood mononuclear cells. LTBI-participants had higher expression of activation markers and cytokines, including IL10, and IFNγ. An exploratory analysis of BCG-recipients with minimal exposure to TB showed absence of CD8+GMM+Granzyme-B+ T cells, lower or equal proportions of Granzyme-B+PD-1+ polyfunctional T cells than TB-resisters and higher or equal than LTBI-participants. In conclusion, high Granzyme-B+PD-1+ T cell responses to M. tuberculosis and, possibly, of CD8+GMM+Granzyme-B+ T cells may be desirable for new TB vaccines.
© 2023 The Authors.

This study aimed to investigate the anti-PD-1 inhibitor pembrolizumab as a potential agent for use in non-muscle-invasive bladder cancer (NMIBC) by conducting a Phase 1 safety run-in study to assess the safety and tolerability of intravesical pembrolizumab after transurethral resection of the bladder tumour (TURBT).
Eligible patients had recurrent NMIBC for which adjuvant treatment post TURBT was a reasonable treatment option, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1 and adequate end-organ function. Pembrolizumab was administered by intravesical instillation once weekly for a total of six doses. Intra-patient dose escalation was performed in three paired patient cohorts with doses starting at 50 mg and increasing through 100 mg to a maximum of 200 mg. Adverse events (AEs) were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.03 with dose limiting toxicity (DLT) defined as a clinically significant, drug-related, Grade 4 haematological or Grade 3 or higher non-haematological toxicity occurring within 7 days of administration of the first treatment at a given dose for that patient.
Six patients were treated with no DLTs seen during dose escalation. Drug-related AEs were of low grade and included dysuria and fatigue. All patients completed six doses of treatment as planned. Pharmacokinetic and pharmacodynamic assays did not detect any pembrolizumab in the serum following repeated intravesical administration, and no changes in peripheral immune cell populations were observed.
Administration of intravesical pembrolizumab was well tolerated and did not raise any safety concerns in patients with NMIBC following TURBT. There was no evidence of systemic absorption or systemic immune effects following intravesical administration. Further studies are required to assess whether intravesical administration has anti-tumour activity.
© 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.

To phenotype transcriptomically M1 macrophages (Mϕ1) and M2 macrophages (Mϕ2) in the endometrium of women with endometriosis.
Prospective experimental study.
University research laboratory.
Six women with endometriosis and five controls without disease, in the secretory phase of the menstrual cycle.
Mϕ1, Mϕ2, uterine natural killer, and T regulatory cells were isolated from human endometrium using a uniquely designed cell-specific fluorescence activating cell sorting panel. Transcriptome profiles were assessed by RNA high sequencing, bioinformatics, and biological pathway analyses.
Differential gene expression between Mϕ1 and Mϕ2 in women with and without endometriosis and in Mϕ1 versus Mϕ2 in each group was determined and involved different biologic and signaling pathways.
Flow cytometry analysis showed no significant differences in total numbers of leukocytes between control and endometriosis groups, although Mϕ1 were higher in the endometriosis group versus controls. Statistical transcriptomic analysis was performed only in Mϕ1 and Mϕ2 populations due to larger sample sizes. Bioinformatic analyses revealed that in women with endometriosis, endometrial Mϕ1 are more proinflammatory than controls and that Mϕ2 paradoxically have a proinflammatory phenotype.
As Mϕ are phenotypically plastic and their polarization state depends on their microenvironment, the altered endometrial environment in women with endometriosis may promote endometrial Mϕ2 polarization and an Mϕ1 proinflammatory phenotype. Moreover, aberrant phenotypes of Mϕ may contribute to abnormal gene expression of the eutopic endometrium and a proinflammatory environment in women with endometriosis relevant to the pathophysiology of the disease and compromised reproductive outcomes.
Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.