PD-1 efficiently inhibits T cell activation even in the presence of co-stimulation through CD27 and GITR.

Cancer immunotherapies targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 revolutionized cancer treatment and instigated various trials to develop new cancer immunotherapies with higher therapeutic efficacy. Agonistic Abs against tumor necrosis factor receptor super family (TNFRSF) molecules are highly expected due to their high potential to enhance survival, proliferation, and effector function of T cells. To date, agonistic antibodies (Abs) against CD27, GITR, OX40, and 4-1BB have been reported to increase the efficacy of anti-PD-1 therapy in animal models and clinical trials of these combinatorial therapies are underway. However, the mechanisms how agonistic Abs against TNFRSF molecules potentiate anti-PD-1 therapy are not well understood. Here we examined the potency of PD-1 to inhibit the antigen-dependent activation of T cells in the presence of co-stimulation through CD27 and GITR by using in vitro and ex vivo co-culture systems of T cells and antigen presenting cells. The cytokine secretion from T cells upon antigen stimulation was strongly augmented by the engagement of CD27 or GITR with their corresponding ligands. Remarkably, PD-1 efficiently inhibited the activation of T cells even in the presence of co-stimulation through CD27 or GITR. Accordingly, cytokine secretion was synergistically augmented when PD-1 blockade was combined with triggering of CD27 or GITR. These results indicate that the triggering of TNFRSF molecules and PD-1 blockade can act on the same individual cells simultaneously to augment the magnitude of T cell activation, providing the rationale for the combinatorial usage of agonistic Abs against TNFRSF molecules and blocking Abs against PD-1 or PD-L1.

PD-1 aborts the activation trajectory of autoreactive CD8+ T cells to prohibit their acquisition of effector functions.

Anti-PD-1 therapy can induce eradication of tumors and immune-related adverse events (irAEs) in humans and model animals. However, how anti-PD-1 therapy modifies cellular phenotypes of CD8+ T cells to destroy tumors and damage self-tissues remains to be clarified. Here we performed single cell mRNA expression profiling of autoreactive CD8+ T cells under or beyond PD-1 suppression in target tissues and reconstructed their activation trajectory. Autoreactive CD8+ T cells went through four activation phases and PD-1 strongly attenuated the transition from the second- to the third-phase, where effector functions were acquired. Shifts in cluster composition of autoreactive CD8+ T cells markedly reflected the severity of autoimmunity. In addition, genes up-regulated along the activation-trajectory in autoimmunity were highly expressed in responders of melanoma patients in anti-PD-1 therapy, suggesting that tumor-specific T cells need to be activated in a similar trajectory to destroy tumors in human patients upon PD-1 blockade. These findings reveal that PD-1 blockade facilitates the activation trajectory of CD8+ T cells to boost their effector functions. Targeted manipulation of the trajectory could lead to new therapeutic opportunities.

TERT promoter methylation is significantly associated with TERT upregulation and disease progression in pituitary adenomas.

PURPOSE: Alterations in the promoter of the telomerase reverse transcriptase (TERT) gene are a major mechanism of upregulating telomerase, which plays a crucial role in tumor development. Mutations in the TERT promoter have been observed in a subset of brain tumors, including adult gliomas and high-grade meningiomas. In pituitary adenomas (PAs), however, abnormalities in TERT are not fully understood. The present study aimed to investigate not only mutational but also methylation changes in the TERT promoter in PAs and to analyze their correlations with clinical variables. METHODS: We retrospectively studied 70 PAs consisting of 53 primary and 17 recurrent samples. Clinical data, including age at surgery, sex, largest tumor dimension, tumor subtype, resection rate, and progression-free survival (PFS), were obtained from medical records. We investigated TERT promoter hotspot mutations via Sanger sequencing and quantified the methylation status of the TERT promoter using methylation-sensitive high-resolution melting analysis (MS-HRM). Additionally, we investigated TERT mRNA expression using real-time quantitative PCR. RESULTS: TERT promoter hotspot mutations were not observed in any PA sample, while 16% of PAs exhibited TERT promoter methylation. PAs with methylated TERT promoters were significantly more likely to show disease progression, shorter PFS, and higher TERT expression levels compared to those with unmethylated promoters. CONCLUSIONS: This is the first study showing that TERT promoter methylation is associated with disease progression and shorter PFS as well as upregulated TERT expression in PAs. Our results suggest that TERT promoter methylation may be a potential biomarker for predicting tumor recurrence in PAs.

Rapidly Progressing Intramedullary Spinal Cord Abscess: A Case Report.

Intramedullary spinal cord abscess is a rare and severe infectious disease characterized by devastating neurological deficits. We report a case of cervical intramedullary spinal cord abscess in a 74-year-old diabetic male with a 3-day history of neck pain and weakness in the right lower extremity. Magnetic resonance imaging revealed a ring-shaped contrast lesion in C3-C6 of the cervical spinal cord with extensive edema. Further, 1 day after admission, he became comatose (Glasgow Coma Scale E1VtM1), and a computed tomography head scan revealed hydrocephalus. Despite emergency ventricular drainage, the patient's level of consciousness remained unchanged. Magnetic resonance imaging performed 1 day after surgery revealed bilateral intracranial extension of the abscess into the thalamus and caudate nucleus. The patient died 19 days after admission. Our report is the first case of extensive brain abscess development over a short period. Based on our experience, prompt administration of antibiotics and emergency abscess drainage of the cervical cord (and ventricular drainage, if necessary) are recommended in cases of neurological deterioration in patients with cervical intramedullary spinal cord abscess.

Double-hit primary central nervous system lymphoma with histogenetically proven bone marrow infiltration: a case report and a review of the literature.

Double-hit lymphoma (DHL) formerly referred to high-grade B-cell lymphoma with concurrent MYC and BCL2 or BCL6 rearrangements, however, the updated 2022 World Health Organization Classification (5th edition online) excludes those with MYC and BCL 6 rearrangements from the high-grade category. DHL confined to the central nervous system (CNS), known as double-hit primary CNS lymphoma (DH-PCNSL), is rare with poorly understood clinical features. Here, we report a case of a 64-year-old man with multiple brain tumors diagnosed with DH-PCNSL who showed bone marrow (BM) infiltration early in the clinical course. The histological diagnosis was high-grade B-cell lymphoma with MYC and BCL6 rearrangements. Fluorodeoxyglucose positron emission tomography (FDG-PET) revealed no abnormal accumulation except in the CNS. The patient received whole-brain radiotherapy following the failure of high-dose methotrexate. After completion of radiotherapy, the patient developed thrombocytopenia, and BM biopsy showed infiltration of DHL cells, which were not detected by repeated FDG-PET. This is the first report of DH-PCNSL where identical gene rearrangements were confirmed in both the resected CNS tumor and BM tissue. Patients with DH-PCNSL require careful follow-up because they may be at a potential risk of BM infiltration, which may be undetectable by FDG-PET, particularly early in the disease course.

Successful Treatment of a CNS Tumor with BCOR Internal Tandem Duplication: A Case Report.

A central nervous system (CNS) tumor with BCL-6 co-repressor (BCOR) internal tandem duplication (CNS tumor with BCOR ITD) is a rare tumor classified as an embryonal tumor by the World Health Organization classification (5th edition), and the prognosis is generally poor. A successfully treated case is reported, and its treatment is discussed. A five-year-old boy presented with a one-month history of headache and vomiting. Magnetic resonance imaging showed a well-demarcated, left-frontal tumor without perifocal edema. The patient underwent complete resection without a neurological deficit. Anti-BCOR antibody showed strong immunoreactivity in tumor nuclei, and the tumor was diagnosed as a CNS tumor with BCOR ITD. The patient received craniospinal irradiation (CSI) comprising 23.4 Gy, followed by a boost to the primary site to a total dose of 30.6 Gy in daily fractions of 1.8 Gy. The chemotherapy comprised four cycles of vincristine, cyclophosphamide, and cisplatin with peripheral blood stem cell rescue. The clinical course was uneventful throughout the treatment, the tumor has not recurred for four years, and no neurological impairment was reported. CSI and multiagent chemotherapy were effective for a CNS tumor with BCOR ITD.

True anaplastic oligoastrocytoma with dual genotype: illustrative case.

BACKGROUND: The revised fourth edition of the World Health Organization classification of central nervous system tumors was published in 2016. Based on this classification, one of the infiltrating glioma entities named "oligoastrocytoma/anaplastic oligoastrocytoma" is discouraged. It is proposed that these mixed gliomas should be classified as diffuse astrocytoma/anaplastic astrocytoma or oligodendroglioma/anaplastic oligodendroglioma when analyzing their genetic alteration. OBSERVATIONS: A 78-year-old female underwent brain computed tomography (CT) because of a traffic accident. Cranial CT revealed a brain tumor in the left temporoparietal lobe; therefore, she was hospitalized. She underwent awake craniotomy. After the operation, she was treated with only local radiotherapy; the authors could not prescribe temozolomide, because she had had levetiracetam-induced pancytopenia. The remaining tumor neuroradiologically disappeared, and she was alive 40 months after the operation without tumor recurrence. LESSONS: Histopathologically, this tumor was diagnosed as an anaplastic oligoastrocytoma with a distinct dual phenotype of astrocytoma and oligodendroglioma components. Genetically, these two components revealed astrocytoma and oligodendroglioma genotypes, respectively. Therefore, the authors considered the integrated diagnosis of the temporal tumor as a true anaplastic oligoastrocytoma with a dual genotype. Interestingly, this case also included an area composed of spindle to oval neoplastic cells that revealed intermediate genetic alterations between astrocytomas and oligodendrogliomas.

Intracytoplasmic dot-like inclusions as cytopathologically useful findings of ependymoma: Case report of adolescent supratentorial anaplastic ependymoma with clear cell morphology.

Pediatric supratentorial ependymomas often have a clear cell morphology and reveal a RELA fusion. When a clear cell neoplasm is intraoperatively diagnosed, intracytoplasmic dot-like inclusions by cytology are a useful cytopathological feature of ependymoma.

PD-1 Primarily Targets TCR Signal in the Inhibition of Functional T Cell Activation.

Cancer-immunotherapy targeting programmed cell death 1 (PD-1) activates tumor-specific T cells and provides clinical benefits in various cancers. However, the molecular basis of PD-1 function is still enigmatic. Especially, it is unclear which signaling pathway PD-1 primarily targets. Besides, the capacity of PD-1 to inhibit the T cell receptor (TCR)-dependent activation of T cells in the presence of co-stimulation is also controversial. Here we used co-culture systems of T cells and antigen-presenting cells with targeted deletion and overexpression of co-receptors and ligands and examined the inhibitory potency of PD-1 against T cell activation upon TCR stimulation with CD28 and ICOS co-stimulation. As an unambiguous criterion of T cell activation, we used the acquisition of cytokine production capacity, which represents one of the most important functions of T cells. PD-1 inhibited functional T cell activation upon TCR stimulation in the absence as well as in the presence of CD28 co-stimulation, indicating that PD-1 can directly inhibit TCR signal. Notably, CD28 co-stimulation rather attenuated the efficiency of PD-1 in inhibiting TCR-dependent functional T cell activation. In addition, PD-1 inhibited TCR-dependent functional T cell activation with ICOS co-stimulation as efficiently as that with CD28 co-stimulation. Furthermore, we found that the maintenance of antigen-induced follicular helper T (TFH) cells that required ICOS co-stimulation was persistently restrained by PD-1 in vivo. These findings indicate that PD-1 primarily targets TCR signal in the inhibition of functional T cell activation. Thus, PD-1 functions as the rheostat of T cell activation rather than an inhibitor of a specific stimulatory co-receptor.