PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells.

CD19-targeting chimeric antigen receptor (CAR) T cells have become an important therapeutic option for patients with relapsed and refractory B cell malignancies. However, a significant portion of patients still do not benefit from the therapy owing to various resistance mechanisms, including high expression of multiple inhibitory immune checkpoint receptors. Here, we report a lentiviral two-in-one CAR T approach in which two checkpoint receptors are downregulated simultaneously by a dual short hairpin RNA cassette integrated into a CAR vector. Using this system, we evaluated CD19-targeting CAR T cells in the context of four different checkpoint combinations-PD-1/TIM-3, PD-1/LAG-3, PD-1/CTLA-4, and PD-1/TIGIT-and found that CAR T cells with PD-1/TIGIT downregulation uniquely exerted synergistic antitumor effects. Importantly, functional and phenotypic analyses suggested that downregulation of PD-1 enhances short-term effector function, whereas downregulation of TIGIT is primarily responsible for maintaining a less differentiated/exhausted state, providing a potential mechanism for the observed synergy. The PD-1/TIGIT-downregulated CAR T cells generated from diffuse large B cell lymphoma patient-derived T cells also showed robust antitumor activity and significantly improved persistence in vivo. The efficacy and safety of PD-1/TIGIT-downregulated CD19-targeting CAR T cells are currently being evaluated in adult patients with relapsed or refractory large B cell lymphoma (ClinicalTrials.gov: NCT04836507).

Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19.

Although most SARS-CoV-2-infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the TNF/IL-1ß-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1ß-driven inflammation, and this was not seen in patients with milder COVID-19. Interestingly, we documented type I IFN-driven inflammatory features in patients with severe influenza as well. Based on this, we propose that the type I IFN response plays a pivotal role in exacerbating inflammation in severe COVID-19.

VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers.

Although immune checkpoint blockade therapies have demonstrated clinical efficacy in cancer treatment, harnessing this strategy is largely encumbered by resistance in multiple cancer settings. Here, we show that tumor-infiltrating T cells are severely exhausted in the microsatellite stable (MSS) colorectal cancer (CRC), a representative example of PD-1 blockade-resistant tumors. In MSS CRC, we found wound healing signature to be up-regulated and that T cell exhaustion is driven by vascular endothelial growth factor-A (VEGF-A). We report that VEGF-A induces the expression of transcription factor TOX in T cells to drive exhaustion-specific transcription program in T cells. Using a combination of in vitro, ex vivo, and in vivo mouse studies, we demonstrate that combined blockade of PD-1 and VEGF-A restores the antitumor functions of T cells, resulting in better control of MSS CRC tumors.

The association between abortion experience and postmenopausal suicidal ideation and mental health: Results from the 5th Korean National Health and Nutrition Examination Survey (KNHANES V).

OBJECTIVE: The association between abortion and postmenopausal mental health has not been clearly established in Asian women. The objective of this study was to evaluate the effect of abortion experiences on suicidal ideation and mental health in Korean postmenopausal women. MATERIALS AND METHODS: This study included 5133 postmenopausal women registered in the Korean National Health and Nutrition Examination Survey between 2010 and 2012. Difference in suicidal ideation according to type and number of abortions was analyzed. We used survey multiple logistic regression analysis to evaluate the effect of abortion experiences on the risk for suicidal ideation expressed as adjusted odd ratios (ORs) with 95% confidence intervals (95%CIs). RESULTS: The risk of suicidal ideation was significantly higher in women who experienced more than three abortions (27.9%). While the incidence of suicidal ideation was not significantly affected by the number of spontaneous abortions (p = 0.718), suicidal ideation was significantly more frequent in women who had undergone ≥ three abortions (p = 0.003). After adjusting for demographic confounding factors, women who underwent ≥ three induced abortions had higher risk for suicidal ideation (OR: 1.510; 95% CI: 1.189-1.919; p = 0.031). This risk remained elevated even after controlling for depression (OR: 1.391; 95% CI: 1.1086-1.871, p = 0.002). Moreover, the risk of experiencing a depressive mood in daily life was also increased with increasing number of induced abortions even after controlling for depression (OR: 1.657; 95% CI: 1.274-2.156, p = 0.002). CONCLUSION: Undergoing three or more induced abortions during reproductive age was associated with postmenopausal suicidal ideation, stress, and depression. However, such association was not noted in those with spontaneous abortion, even in women with more miscarriages. Thus, clinicians should evaluate depression and suicidal ideation in women with multiple induced abortions.

Abdominal wall endometriosis treatment by ultrasound-guided high-intensity focused ultrasound ablation: a case report.

Abdominal wall endometriosis (AWE) occurs in about 0.1% of people with endometriosis, and is often diagnosed postoperatively. Surgical resection is generally used to treat AWE. We successfully treated AWE with ultrasound-guided high-intensity focused ultrasound therapy (USgHIFU). A 37-year-old Korean female presented with a palpable subcutaneous nodule associated with cyclic pain and swelling during menstruation. She was recommended surgical excision three months ago. She had a history of laparoscopic surgery for endometriosis 4 years ago and was interested in less invasive methods of treatment. The 0.9 cm painful nodule was observed as a low-echoic shadow in transabdominal ultrasonography and as an iso-signal in T1 MRI images. USgHIFU treatment was performed under light sedation and completed when the hyperechoic area covered the entire lesion. HIFU treatment was effective without any postoperative complications such as blisters or skin burns. The lesion showed changes in hyper-intensity signal on T1 MRI images. Physical examination showed absence of pain or tenderness and three months later, the painful nodule shrunk, and the menstrual cyclic pain associated with the nodule disappeared. In conclusion, USgHIFU may represent an effective therapy for AWE.