IL-2Rα-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+ T cells.

To avoid regulatory T cell promotion and vascular toxicity, the interleukin-2 receptor-ß/interleukin-2 receptor-γ (IL-2Rßγ)-biased approach is used by most IL-2 analogs in immuno-oncology. However, recent clinical disappointments in these IL-2 agonists have questioned this strategy. Here we show that both wild-type (IL-2wt) and IL-2Rßγ-attenuated (IL-2α-bias) agonists that preserve IL-2Rα (CD25) activities can effectively expand tumor-specific CD8+ T cells (TSTs) and exhibit better antitumor efficacy and safety than the 'non-α' counterpart (IL-2nα). Mechanistically, TSTs coexpress elevated CD25 and PD-1 and are more susceptible to stimulation by IL-2Rα-proficient agonists. Moreover, the antitumor efficacy of anti-PD-1 depends on activation of PD-1+CD25+ TSTs through autocrine IL-2-CD25 signaling. In individuals with cancer, a low IL-2 signature correlates with non-responsiveness to anti-PD-1 treatment. In mouse models, IL-2α-bias, but not IL-2nα, restores the IL-2 signature and synergizes with anti-PD-1 to eradicate large established tumors. These findings underscore the indispensable function of CD25 in IL-2-based immunotherapy and provide rationales for evaluating IL-2Rα-biased agonists in individuals with cancer.

Optimal target saturation of ligand-blocking anti-GITR antibody IBI37G5 dictates FcγR-independent GITR agonism and antitumor activity.

Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a co-stimulatory receptor and an important target for cancer immunotherapy. We herein present a potent FcγR-independent GITR agonist IBI37G5 that can effectively activate effector T cells and synergize with anti-programmed death 1 (PD1) antibody to eradicate established tumors. IBI37G5 depends on both antibody bivalency and GITR homo-dimerization for efficient receptor cross-linking. Functional analyses reveal bell-shaped dose responses due to the unique 2:2 antibody-receptor stoichiometry required for GITR activation. Antibody self-competition is observed after concentration exceeded that of 100% receptor occupancy (RO), which leads to antibody monovalent binding and loss of activity. Retrospective pharmacokinetics/pharmacodynamics analysis demonstrates that the maximal efficacy is achieved at medium doses with drug exposure near saturating GITR occupancy during the dosing cycle. Finally, we propose an alternative dose-finding strategy that does not rely on the traditional maximal tolerated dose (MTD)-based paradigm but instead on utilizing the RO-function relations as biomarker to guide the clinical translation of GITR and similar co-stimulatory agonists.

Artificial intelligence and polyp detection in colonoscopy: Use of a single neural network to achieve rapid polyp localization for clinical use.

BACKGROUND AND AIM: Artificial intelligence has been extensively studied to assist clinicians in polyp detection, but such systems usually require expansive processing power, making them prohibitively expensive and hindering wide adaption. The current study used a fast object detection algorithm, known as the YOLOv3 algorithm, to achieve real-time polyp detection on a laptop. In addition, we evaluated and classified the causes of false detections to further improve accuracy. METHODS: The YOLOv3 algorithm was trained and validated with 6038 and 2571 polyp images, respectively. Videos from live colonoscopies in a tertiary center and those obtained from public databases were used for the training and validation sets. The algorithm was tested on 10 unseen videos from the CVC-Video ClinicDB dataset. Only bounding boxes with an intersection over union area of > 0.3 were considered positive predictions. RESULTS: Polyp detection rate in our study was 100%, with the algorithm able to detect every polyp in each video. Sensitivity, specificity, and F1 score were 74.1%, 85.1%, and 83.3, respectively. The algorithm achieved a speed of 61.2 frames per second (fps) on a desktop RTX2070 GPU and 27.2 fps on a laptop GTX2060 GPU. Nearly a quarter of false negatives happened when the polyps were at the corner of an image. Image blurriness accounted for approximately 3% and 9% of false positive and false negative detections, respectively. CONCLUSION: The YOLOv3 algorithm can achieve real-time poly detection with high accuracy and speed on a desktop GPU, making it low cost and accessible to most endoscopy centers worldwide.

Estrogen-mediated regulation of mitochondrial gene expression.

Estrogens, in particular 17ß-estradiol, are well-known regulators of essential cellular functions; however, discrepancies remain over the mechanisms by which they act on mitochondria. Here we propose a novel mechanism for the direct regulation of mitochondrial gene expression by estrogen under metabolic stress. We show that in serum-depleted medium, estrogen stimulates a rapid relocation of estrogen receptor-α to mitochondria, in which it elicits a cellular response, resulting in an increase in mitochondrial RNA abundance. Mitochondrial RNA levels are regulated through the association of estrogen receptor-α with 17ß-hydroxysteroid dehydrogenase 10, a multifunctional protein involved in steroid metabolism that is also a core subunit of the mitochondrial ribonuclease P complex responsible for the cleavage of mitochondrial polycistronic transcripts. Processing of mitochondrial transcripts affects mitochondrial gene expression by controlling the levels of mature RNAs available for translation. This work provides the first mechanism linking RNA processing and estrogen activation in mitochondrial gene expression and underscores the coordinated response between the nucleus and mitochondria in response to stress.

Heterozygosity for Roquinsan leads to angioimmunoblastic T-cell lymphoma-like tumors in mice.

Angioimmunoblastic T-cell lymphoma (AITL) is the second most common peripheral T-cell lymphoma with unusual clinical and pathologic features and a poor prognosis despite intensive chemotherapy. Recent studies have suggested AITL derives from follicular helper T (T(FH)) cells, but the causative molecular pathways remain largely unknown. Here we show that approximately 50% of mice heterozygous for the "san" allele of Roquin develop tumors accompanied by hypergammaglobulinemia by 6 months of age. Affected lymph nodes displayed the histologic features diagnostic of AITL, except for the presence of expanded FDC networks. Accumulation of T(FH) cells preceded tumor development, and clonal rearrangements in the TCR-ß genes were present in most tumors. Furthermore, T(FH) cells exhibited increased clonality compared with non-T(FH) cells from the same lymph nodes, even in the absence of tumors. Genetic manipulations that prevent T(FH) development, such as deletion of ICOS, CD28, and SAP, partially or completely abrogated tumor development, confirming a T(FH)-derived origin. Roquin(san/+) mice emerge as a useful model to investigate the molecular pathogenesis of AITL and for preclinical testing of therapies aimed at targeting dysregulated T(FH) cells or their consequences.