Citations

Abstract Description The PD-L1/PD-1 receptor pathway allows cancer cells to evade immune surveillance, yet only a small percentage of patients benefit from PD-1/PD-L1 inhibitors. This limited efficacy is likely due to gaps in our understanding of PD-1/PD-L1 biology, particularly the lesser-known intracellular roles of PD-L1 compared to its extracellular interactions. Our research found that intracellular PD-L1 functions as an RNA-binding protein, interacting with NBS1 and BRCA1 mRNAs to protect them from degradation, thereby increasing cellular resistance to DNA damage. Given that current PD-1/PD-L1 inhibitors have little effect on intracellular PD-L1, we aimed to develop new drugs targeting this pathway. We created a novel PD-L1 antibody that disrupts the binding of PD-L1 to CMTM6, promoting PD-L1 degradation via the lysosome instead of blocking the PD-1/PD-L1 interaction. This mechanism enables the antibody to inhibit intracellular PD-L1 functions, something conventional immunotherapies cannot achieve. In vivo studies demonstrated that our antibody significantly sensitized tumors to radiation and chemotherapy in patient-derived xenograft models. In a humanized immune-competent triple-negative breast cancer PDX model, it outperformed existing PD-L1 inhibitors, suggesting it enhances anti-tumor immunity through PD-L1 degradation. This novel antibody offers a promising dual approach by targeting both intracellular and extracellular PD-L1, providing a compelling new strategy for cancer therapy. Funding Sources This work was supported in part by the American Society for Radiation Oncology, the National Cancer Institute of the National Institutes of Health under Award Number CA203561, P50CA116201, K12 HD065987, HALT Cancer at X, NCI R21 CA197878 (HD), R01-AI095239 and NIAID R01 AI095239. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Abstract Description Measles is a highly contagious virus that presents as fever, cough, and a rash that spreads from the face to the rest of the body. Other serious complications, such as pneumonia, deafness, and encephalitis, can occur in immunocompromised and unvaccinated populations. Although there is an effective vaccine, there are currently no FDA-approved antivirals for measles. Moreover, there has been an increased incidence of measles outbreaks in the United States. Two main targets for measles virus antiviral therapies include its surface glycoproteins, hemagglutinin (H) and fusion (F), which mediate attachment and fusion of the viral and cellular membranes, respectively. After binding of the H-protein to SLAM or nectin-4 on the host cell surface, the F-protein undergoes a conformational change to initiate a fusion event. Using a hybridoma-based approach, we isolated a panel of human monoclonal antibodies from the peripheral blood B cells of vaccinated or naturally infected measles donors that bind either the H or F proteins. These antibodies potently neutralize against a pseudotyped vesicular stomatitis virus expressing measles H and F proteins in vitro by inhibiting viral attachment or fusion. Structural studies will identify critical contact residues between these antibodies and their respective antigens and inform mutational escape assays for likely sites for immune evasion. The protective efficacy of these antibodies will also be assessed using a cotton rat in vivo model. Topic Categories Vaccines and Immunotherapy (VAC)

Abstract Description Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy derived from transformed B cells of germinal center (GC) or post-GC origin. DLBCL incidence is elevated in immunodeficient persons with reduced T cells, such as among HIV+ patients. Yet a causal link between T cell deficiency and DLBCL is incompletely understood. Using a mouse model of spontaneous DLBCL, we show that suboptimal T cell function, but neither zero nor full T cell function, can be a driver of B cell lymphomagenesis. In CD3δ-/- mice, which exhibit reduced number, signaling, and function of T cells, we observed progressive disruption of splenic architecture and eventual DLBCL development with ∼100% incidence. In contrast, lymphoma did not develop in wild-type mice, or CD3e-/-z-/- mice with complete T cell absence. This showed that poor-but-positive suboptimal T cells were required for GC B cell transformation and outgrowth. Mechanistically, CD3δ-/- mice exhibited altered GC dynamics at steady state and in response to immunization. Compared with wild-type mice, CD3δ-/- mice had a diminished T follicular regulatory (TFR) compartment and exhibited defective T follicular helper (TFH) cell differentiation when antigen challenged, indicating compromised regulation of the GC reaction. Indeed, defective GC B cell entry and differentiation was also observed. Our data thus suggest that suboptimal function of T helper subsets can lead to dysegulated GC reactions and B cell lymphomagenesis. Funding Sources Supported by AAI Intersect Fellowship Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)

PURPOSE Neoadjuvant immune checkpoint inhibitors (nICIs) have demonstrated high response rates in deficient mismatch repair/microsatellite instability–high (dMMR/MSI-H) gastroesophageal adenocarcinoma (GEA). The NEONIPIGA and INFINITY trials demonstrated high rates of pathologic complete response (pCR) in this patient population. Furthermore, the INFINITY trial explored the feasibility of managing these patients nonoperatively, demonstrating promising results. This study aimed to evaluate clinical outcomes of nICIs in resectable dMMR/MSI-H GEA, with a focus on the feasibility of nonoperative management (NOM). MATERIALS AND METHODS This retrospective cohort study included patients with resectable dMMR/MSI-H GEA and treated with nICIs ± surgery at the Mayo Clinic. Patients were identified from institutional records, and clinical data were retrospectively reviewed. Primary outcomes were clinical complete response (cCR) and pCR. Secondary outcomes included event-free survival (EFS), radiologic complete response (rCR), and immune-related adverse events (irAEs). RESULTS A total of 26 patients treated between April 1, 2017, and July 30, 2025, were identified. Nine patients (34.6%) underwent surgery, of whom six (66.7%) achieved pCR. Seventeen patients (65.4%) pursued NOM, with 10 (71.4%) of 14 evaluable patients achieving cCR and 14 (82.4%) of 17 evaluable achieving rCR. One patient who initially achieved cCR had a local recurrence on surveillance endoscopy and underwent salvage endoscopic resection. At a median follow-up of 19.3 months, 15 (88.2%) of 17 patients in the NOM cohort were alive and metastasis-free, with EFS rates of 87.3% at 12 and 24 months for all patients. irAEs occurred in nine patients (34.6%), with no grade ≥3 toxicities. CONCLUSION In this retrospective cohort study, nICIs led to high cCR and pCR rates in resectable dMMR/MSI-H GEA, supporting the use of immune checkpoint inhibitors in this setting and the feasibility of NOM in select patients.

Importance The ideal duration of androgen deprivation therapy (ADT) for treating localized prostate cancer is unknown due to variable adherence and treatment durations tested in clinical trials. Objective To determine the ideal duration of ADT for patients with prostate cancer treated with radiotherapy. Data Sources This individual patient data meta-analysis of 13 randomized phase 3 clinical trials evaluated the use of radiotherapy alone or with ADT. It included patients with a median follow-up of 11.3 (IQR, 9.5-14.5) years and ADT duration of 0 to 36 months. Most patients (7392 [72%]) included had National Comprehensive Cancer Network high-risk or very high-risk disease. Study Selection For this meta-analysis, a systematic literature search from 1980 to 2020 was performed in trial registries (Cochrane Central Register of Controlled Trials and ClinicalTrials.gov), MEDLINE (1966-2020), Embase (1982-2020), Web of Science, and Scopus to identify trials. Data Extraction and Synthesis Intention-to-treat and as-treated analyses were performed. The number needed to treat to prevent 1 distant metastasis at 10 years was calculated based on prognostic risk group. The analyses were conducted from January 5 to August 15, 2023. Main Outcomes and Measures The primary end point for this study was overall survival, defined as time to death or last follow-up from randomization. Secondary end points included biochemical recurrence, distant metastasis (DM), prostate cancer–specific mortality, and other-cause mortality. Results The median (IQR) age among the 10 266 male patients was 70 (65-74) years. Longer durations of ADT were associated with nonlinear improvement in relative benefits of DM, prostate cancer–specific mortality, and overall survival, with reduced estimated benefits beyond 9 to 12 months of ADT based on the end point. There was a near-linear increase in other-cause mortality associated with long-term ADT use (hazard ratio, 1.28; 95% CI, 1.09-1.50; P = .002 for 28 vs 0 months of ADT). The optimal ADT duration based on 10-year DM was 0, 6, 12 months, and undefined for patients with 1 intermediate-risk factor, 2 or more intermediate-risk factors, and National Comprehensive Cancer Network high-risk and very high-risk disease, respectively. Conclusions and Relevance The results of this meta-analysis suggest that, for men with localized prostate cancer treated with definitive radiotherapy and ADT, there are relative and absolute benefits from increasing durations of ADT that help provide individualized risk estimates.

Aging plays a major role in the development of numerous chronic diseases, one of which is a marked decline in skeletal health. Beyond diminishing bone mass and strength, mammals of advanced age experience a decline in skeletal mechanotransduction—that is, the ability of the skeleton to respond adaptively to mechanical perturbation. One possibility for the loss of mechanotransduction in bone with aging is an age-associated increase in the population density of senescent cells—those cells that have undergone irreversible cell cycle arrest, resistance to apoptosis, and production of a modified secretome (the SASP) that has damaging effects to nearby healthy (non-senescent) cells. We investigated whether the presence of senescent cells might drive some of the diminished mechanical response observed in aged bone, by testing the hypothesis that the clearance of senescent cells via intermittent senolytic treatment promotes mechanical responsiveness in an aged skeleton. C57BL/6 mice aged 6 months and 22 months were treated weekly with the senolytic cocktail Dasatinib and Quercetin (D + Q) for 1 month, then subjected to low level in vivo mechanical loading of the ulna for 1 week. The 6-month-old mice exhibited a doubling of load-induced ulnar periosteal bone formation when treated with D + Q, compared to vehicle-treated mice, but the periosteal response to loading was not significantly altered by D + Q in the aged (22-month) mice. We further probed the efficacy of D + Q in mechanotransduction by switching to an endocortical model—the axial tibia loading system. Here, the 22-month-old mice had nearly double the load-induced endocortical bone formation compared to vehicle-treated mice. We further assayed the cortical bone gene expression profile in loaded and control tibias from treatment-naïve 6-month and 22-month mice, to determine whether there is significant overlap between mechanically induced signaling genes and SASP genes. We found significant load-induced changes among several SASP genes, suggesting that inhibition of the SASP (i.e., senomorphics) might interfere with mechanical signaling from otherwise healthy cells. In summary, clearance of senescent cells via intermittent D + Q treatment is effective at improving endocortical mechanical responsiveness in the aged skeleton, which is commonly diminished throughout the course of aging.

Background: Inappropriate facial scarring can lead to significant physical and psychosocial morbidity. There is a need to better understand how scar perception varies across ethnic groups, and how it impacts broader quality-of-life domains such as career and sexual well-being. This study evaluates White and Asian patients’ perceptions of facial scars related to symptoms, appearance, psychosocial health, and career/sexual well-being. Methods: Facial surgery patients from 5 providers were recruited to complete the SCAR-Q and Career/Sexual Well-Being (CS) scales through phone or email. Higher scores on both assessments indicate more positive patient perceptions. Results: Among the 147 respondents, 50.3% were Asian and 49.7% were White. Procedures included blepharoplasty (n=56), rhinoplasty (n=20), eyelid revision (n=19), facelift (n=18), Mohs surgery (n=7), chin augmentation (n=6), craniotomy (n=6), and other facial procedures (n=16). White patients scored significantly higher than Asian patients on the SCAR-Q total (median=260 versus 234), appearance (76 versus 59), psychosocial (100 versus 87), and CS (16 versus 12.5) scales ( P =0.004, P <0.001, P =0.026, and P <0.001, respectively). Symptom scores positively correlated with time since surgery in both groups (Asian: r =0.326, P =0.004; White: r =0.319, P =0.011). Conclusions: Asian patients reported more negative perceptions of scar appearance, symptoms, psychosocial impact, and career/sexual well-being than White patients. These findings underscore the importance of tailored follow-up care and counseling to address ethnic differences in scar perception and quality-of-life outcomes.

ABSTRACT We present the case of a 28‐year‐old right‐handed woman with medically refractory focal epilepsy. Her seizure semiology and electroencephalography (EEG) indicated a seizure onset zone in the right central‐parietal area. However, both MRI and PET scans were unremarkable, showing no focal lesions or areas of altered metabolism. Intracranial monitoring, with extensive evaluation of both hemispheres, confirmed the seizure onset zone in the right central‐parietal region. This area not only served as the site of seizure onset but also encompassed the primary sensory cortex.