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Simple Summary: Many breast cancers do not respond to immune checkpoint inhibitor therapy, even when combined with the standard of care chemotherapy. Here, we sought to identify compounds that enhance T-cell-mediated toxicity in tumor cells using a high-throughput screen of known anti-cancer drugs. Beginning with a library of over 400 FDA-approved or investigational compounds, we chose four chemotherapy agents for detailed mechanistic follow-up. We describe potential immunostimulatory properties of paclitaxel, bleomycin sulfate, ispinisib, and etoposide. Ultimately, these studies provide insight into the potential immunostimulatory properties of the chosen follow-up compounds and suggest avenues for future investigations into optimizing chemotherapy partners to use with ICI. Background: Triple-negative breast cancers (TNBCs) typically have a greater immune cell infiltrate and are more likely to respond to immune checkpoint inhibition (ICI) than ER+ or HER2+ breast cancers. However, there is a crucial need to optimize combining chemotherapy strategies with ICI to enhance overall survival in TNBC. Methods: Therefore, we developed a high-throughput co-culture screening assay to identify compounds that enhance CD8+ T-cell-mediated tumor cell cytotoxicity. Over 400 FDA-approved compounds or agents under investigation for oncology indications were included in the screening library. Results: Four chemotherapy agents were chosen as priority hits for mechanistic follow-up due to their ability to enhance T-cell-mediated cytotoxicity at multiple doses and multiple time points: paclitaxel, bleomycin sulfate, ispinesib, and etoposide. Lead compounds affected the expression of MHCI, MHCII, and PD-L1 and induced markers of immunogenic cell death (extracellular ATP or HMGB1). Conclusions: Based on the ability to increase tumor cell susceptibility to T-cell-mediated cytotoxicity while minimizing T-cell toxicity, bleomycin was identified as the most promising lead candidate. Overall, the results of these studies provide mechanistic insight into potential new chemotherapy partners to enhance anti-PD-1 efficacy in TNBC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Triple-negative breast cancer (TNBC) is a challenging-to-treat subtype of breast cancer with limited treatment options beyond standard chemotherapy and surgery. The introduction of immune checkpoint inhibitor (ICI) therapy with anti-PD-1 for the treatment of TNBC represents a great advance in the field, yet few patients achieve long-lasting responses to therapy. The goal of this review is to discuss key efforts to improve ICI response rates in TNBC patients. The three conceptual strategies discussed include improving patient selection, identifying existing therapies that may enhance anti-PD-1 therapy, and identifying new immunotherapy strategies together outside of the PD-1 axis. The introduction of anti-programmed cell death protein-1 (anti-PD-1) to the clinical management of triple-negative breast cancer (TNBC) represents a breakthrough for a disease whose treatment has long relied on the standards of chemotherapy and surgery. Nevertheless, few TNBC patients achieve a durable remission in response to anti-PD-1, and there is a need to develop strategies to maximize the potential benefit of immune checkpoint inhibition (ICI) for TNBC patients. In the present review, we discuss three conceptual strategies to improve ICI response rates in TNBC patients. The first effort involves improving patient selection. We discuss proposed biomarkers of response and resistance to anti-PD-1, concluding that an optimal biomarker will likely be multifaceted. The second effort involves identifying existing targeted therapies or chemotherapies that may synergize with ICI. In particular, we describe recent efforts to use inhibitors of the PI3K/AKT or RAS/MAPK/ERK pathways in combination with ICI. Third, considering the possibility that targeting the PD-1 axis is not the most promising strategy for TNBC treatment, we describe ongoing efforts to identify novel immunotherapy strategies. [ABSTRACT FROM AUTHOR]

Th17 cells (producing IL-17) and Th9 cells (producing IL-9) exhibit functional plasticity, and their role in tumorigenicity is controversial. Th17/IL-17 and Th9/IL-9 exhibit critical, but often opposing, roles in tumor progression. In this issue of the JCI, Salazar et al. show that while IL-17 and IL-9 induced distinct but complementary molecular pathways, both cytokines also induced epithelial-mesenchymal transition (EMT) in lung cancer cells and promoted metastatic spreading. A key question before us now is whether IL-9 and IL-17 contribute to tumor progression in a sequential and stage-specific manner within the tumor microenvironment., Th cell subsets play various roles in cancer T lymphocytes of the adaptive immune system have multifaceted roles in cancer. Following activation, [CD4.sup.+] Th cells can differentiate into various Th [...]

Simple Summary: Patient-derived xenografts (PDX) are valuable models in preclinical oncology drug development. However, they are not well suited for testing immune-based therapies. In contrast, when humanized mice are developed by xenotransplantation of irradiated mice with human CD34+ stem cells to allow for the growth of human tumor tissue in the context of a humanized immune system, it is possible to evaluate the response to both targeted therapy and immune therapy. Unfortunately, humanized mice transplanted with human PDX tissue frequently develop graft-versus-host disease (GVHD). Here, we optimized a protocol for generating humanized PDX mouse models with considerably reduced development of GVHD, making preclinical trials with immune checkpoint inhibitors possible. Current methodologies for developing PDX in humanized mice in preclinical trials with immune-based therapies are limited by GVHD. Here, we compared two approaches for establishing PDX tumors in humanized mice: (1) PDX are first established in immune-deficient mice; or (2) PDX are initially established in humanized mice; then established PDX are transplanted to a larger cohort of humanized mice for preclinical trials. With the first approach, there was rapid wasting of PDX-bearing humanized mice with high levels of activated T cells in the circulation and organs, indicating immune-mediated toxicity. In contrast, with the second approach, toxicity was less of an issue and long-term human melanoma tumor growth and maintenance of human chimerism was achieved. Preclinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with PDX tumors established from tumors with limited CD8+ T cell content. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in humanized mice before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response. [ABSTRACT FROM AUTHOR]

Several lines of evidence suggest that tumor cells show elevated activity of the NF-κB transcription factor, a phenomenon often resulting from constitutive activity of IκB kinase β (IKKβ). However, others have found that loss of NF-κB activity or IKKβ is tumor promoting. The role of NF-κB in tumor progression is therefore controversial and varies with tumor type. We sought to more extensively investigate the role IKKβ in melanoma tumor development by specifically disrupting Ikkb in melanocytes in an established mouse model of spontaneous melanoma, whereby [HRas.sup.V12] is expressed in a melanocyte-specific, doxycycline-inducible manner in mice null for the gene encoding the tumor suppressor inhibitor cyclin-dependent kinase 4/alternative reading frame (Ink4a/Arf). Our results show that Ink4a/[Arf.sup.[-/-]] mice with melanocyte-specific deletion of Ikkb were protected from [HRas.sup.V12]-initiated melanoma only when p53 was expressed. This protection was accompanied by cell cycle arrest, with reduced cyclin-dependent kinase 2 (Cdk2), Cdk4, Aurora kinase A, and Aurora kinase B expression. Increased p53-mediated apoptosis was also observed, with decreased expression of the antiapoptotic proteins Bcl2 and survivin. Enhanced stabilization of p53 involved increased phosphorylation at Ser15 and reduced phosphorylation of double minute 2 (Mdm2) at Ser166. Together, our findings provide genetic and mechanistic evidence that mutant HRas initiation of tumorigenesis requires Ikkβ-mediated NF-κB activity., Introduction A germline mutation or deficiency in the gene that encodes inhibitor cyclin-dependent kinase 4/alternative reading frame (Ink4a/Arf), a tumor suppressor and inhibitor of the cell cycle, is frequently observed [...]

Un peu partout dans le monde, les aménagistes des pêches utilisent souvent des rondins pour réaliser des mouilles pour les salmonidés, souvent pour compenser l'absence de grands débris ligneux (LWD) due à la déforestation ou à d'autres perturbations des forêts alluviales. Des mesures des LWD réalisées sur 11 ruisseaux de montagne du Colorado drainant de vieilles forêts de résineux (Picea - Abies) montrent qu'ils sont à l'origine de la plupart des mouilles. Les morceaux qui contribuent à la formation des mouilles sont, en moyenne, plus grands que ceux qui n'en forment pas. La plupart enjambe le chenal perpendiculairement à l'écoulement et forme des mouilles de chute («plunge pool») et des mouilles de retenue («dammed pool»). Les aménagistes des pêches qui utilisent des troncs perpendiculaires à l'écoulement pour réaliser des mouilles considèrent généralement que cette addition d'habitat améliore la survie des salmonidés résidents pendant les périodes critiques comme l'hiver. Une expérience de longue durée, réalisée pour tester cette hypothèse dans six ruisseaux de montagne du Colorado, a montré que les populations de truites résidentes augmentaient rapidement et significativement dans des portions expérimentales de 250m, par rapport à des témoins adjacents. Cependant, des mesures de la dispersion réalisées par des piégeages et des recaptures de truites marquées ont montré que les mouilles formées par des troncs augmentent les populations de truites adultes en permettant aux truites qui étaient en phase de déplacement de rester dans les portions expérimentales plutôt qu'en améliorant la survie hivernale sur place, comme le décrivent d'autres auteurs. La recherche sur les salmonidés d'eau courante non migrateurs et leur gestion a jusqu'à présent été marquée par un modèle impliquant des déplacements limités, ce qui implique que les adultes soient relativement sédentaires. Cependant, l'analyse d'études antérieures sur les déplacements démontre que la plupart des expérimentateurs ne s'intéressent qu'aux poissons recapturés dans les portions où ils ont été relâchés, ce qui est critiquable si l'on souhaite mettre des mouvements en évidence. Le fait que les poissons présentent des déplacements conséquents a des implications importantes pour l'amélioration et la restauration de l'habitat, et plaide pour une gestion prenant en compte le bassin versant.

Background Current melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort. Methods Rabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30µg), melphalan (12.5µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction. Patients: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan. Results Intravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90 across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%–79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 μV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged. Conclusions Taken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective. [ABSTRACT FROM AUTHOR]