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Abstract Background Metastatic RCC has a poor prognosis. Despite improvement in treatment outcomes with ICB and targeted therapy, many patients fail to respond to first line therapy and immune mediated adverse events(irAE) remains a major challenge, often leading to treatment discontinuation. Therefore, mitigating irAE without compromising antitumor immunity is a critical unmet need. Tryptophan microbial metabolic pathway is known to play a major role in immune homeostasis through its action on Aryl hydrocarbon receptor (AhR) balancing immune suppresser with immune effector responses. We hypothesize that microbial metabolism of tryptophan to indole metabolites may play a role in ICB resistance as well in irAE, identification of which may help us predict patients most likely to respond, without life threatening toxicity. Methods We prospectively collected paired stool and blood samples of treatment naïve metastatic RCC patients, treated with ICB +/- Tyrosine kinase inhibitors (TKI) at treatment initiation and at time of first response assessment (12+/-3 weeks). We evaluated stool metagenomics and untargeted stool and plasma metabolomics among responders (R) and non-responders (NR). We focused on kynurenine/tryptophan and indoles/tryptophan ratio to evaluate differential host and microbial metabolism of tryptophan. A responder was classified as progression free survival (PFS) greater than 6 months while patients with grade 3 or higher irAE was classified as serious IrAE. Results Among 120 patients accrued, 49 were treated with combination ICB, while 71 patients were treated with ICB + TKI. Median follow up was 27 months. 28 patients (23%) had a Grade 3 or higher irAE. 3 patients died from complications attributable to irAE. The median duration to development of any irAE was 3.5 months. Using negative binomial regression model evaluating baseline relative abundance of microbial tryptophan metabolites that were associated both with response as well as serious irAE, we noted significant higher abundance of Indole acetic acid (IAA), indole acetonitrile(ACN), indole acetyl phenylalanine (IAAP)and IAA/kynurenine (Kyn) and lower abundance of tryptophol, indole 3 pyruvic (IPA), (coefficient of 6.4, 1.8, 7.15, 4.6, 0.04, 0.46, with adj p value < 0.05) with serious irAE as well as ICB resistance (Coefficient-5.42, 1.83, 6.15, 4.05, 0.03, 0.4, P < .05). Conclusions This is one of the first studies evaluating microbial metabolic pathways that may play a role in predicting patients who are more likely to respond with lower likelihood of serious irAE in RCC, thus helping to identify strategies to decouple tumor immunity from autoimmunity to improve ICB outcomes. Further the results can be extrapolated to many other solid tumor treated with immunotherapy, as tryptophan metabolism plays a immune homeostatic role across cancers.

Abstract Background Epigenetic dysregulation, including accumulation of Histone H3 lysine 27 acetylation (H3K27ac), is a hallmark of pVHL-deficient clear cell Renal Cell Carcinomas (ccRCCs). H3K27ac is associated with transcriptional activation and its accumulation at cis-regulatory elements (eg, promoters and enhancers/super-enhancers) marks key oncogenes and regulators of cellular identity in many cancers. In ccRCC, specific alterations in H3K27ac have been linked to tumorigenesis and metastatic progression. Importantly, these earlier studies largely relied on the HIF2α-dependent 786-O cells (or their metastatic derivatives), perhaps, missing the importance of HIF-independent epigenetic programs. Altogether, we hypothesized that H3K27ac marks critical genes in pVHL-deficient ccRCCs that sustain tumorigenic and metastatic programs via both HIF-dependent and independent mechanisms. Methods Using an in vivo positive selection ORF screen in poorly tumorigenic pVHL-proficient cells and cell-based mechanistic studies in pVHL-deficient cells, we discovered that the aspartate (Asp) and glutamate (Glu) transporter, SLC1A1/EAAT3, is a metabolic oncogenic dependency in ccRCC. Results pVHL loss promotes HIF-independent SLC1A1 expression via H3K27ac dysregulation. SLC1A1 inactivation, using either genetic or pharmacological approaches, depletes Asp/Glu-derived metabolites [eg, Tricarboxylic acid (TCA) cycle and nucleotide intermediates], impedes ccRCC growth, and sensitizes ccRCCs to anti-metabolite drugs (eg, glutaminase blockers). In human tumors, higher SLC1A1 expression is associated with reduced immune infiltration, oncogenic metabolic programs, and advanced stage/metastatic disease. Finally, in ccRCC animal models, SLC1A1 inactivation diminishes lung metastasis and the outgrowth of established renal tumors. Conclusions Altogether, our studies credential SLC1A1 as a novel, actionable, HIF-independent, metabolic dependency in pVHL-deficient ccRCCs.

Abstract Background Metastatic renal cell carcinoma (mRCC) is a molecularly heterogeneous disease commonly driven by somatic mutations in genes such as VHL, PBRM1, and BAP1. Although next-generation sequencing (NGS) is the gold standard for identifying such mutations, it remains costly and logistically challenging. Given that genetic alterations often lead to morphological changes, we hypothesized that an artificial intelligence (AI) model applied to hematoxylin and eosin (H&E)-stained whole-slide images (WSIs) could predict underlying somatic mutations. Methods We identified consecutive patients with mRCC who had undergone clinical NGS and had available H&E-stained histopathology slides. Patients with somatic alterations in at least one target gene were annotated. WSIs were tiled into non-overlapping 256 × 256-pixel patches. Background tiles were excluded based on brightness. Across 160 total WSIs, 3 slides had no valid tissue tiles and were excluded. The final dataset included 157 slides with usable content. From 69 672 tile attempts, 28 924 tiles (41.5%) passed quality filters and were used for model development. Two modeling pipelines were implemented: (1) slide-level, aggregating global features from WSIs, and (2) tile-level, embedding and classifying each tile with prediction aggregation at the slide level. Embeddings were generated using DINOv2 and the GigaPath foundation model. To evaluate model performance, we used receiver operating characteristic (ROC) curves and computed the area under the curve (AUC) for both slide-level and tile-level pipelines. ROC analysis was applied at both the tile level and the patient-aggregated level. Principal component analysis (PCA) was used for embedding visualization. Violin plots summarized patient-level AUCs across genes. Results A total of 157 WSIs (one per patient) were analyzed. The cohort included 83 VHL with pathogenic variants (PV) (52.9%) and 74 VHL-wild type (47.1%), along with PVs in: PBRM1 (48/157, 30.6%), BAP1 (9/157, 5.7%), PTEN (8/157, 5.1%), TSC1 (7/157, 4.5%), KDM5C (14/157, 8.9%), SETD2 (27/157, 17.2%), MTOR (8/157, 5.1%), TERT (19/157, 12.1%), and NF2 (2/157, 1.3%). Slide-level modeling demonstrated limited performance in mutation prediction. However, tile-level modeling substantially improved performance. The ROC curve for tile-level VHL prediction achieved AUC = 0.7206. Other tile-based AUCs included PBRM1 (0.76), PTEN (0.80), BAP1 (0.69), TSC1 (0.70), and NF2 (0.62), while lower performance persisted for MTOR (0.25), TERT (0.46), and KDM5C (0.47). PCA of tile embeddings revealed partial clustering by mutation status, and heatmaps localized high-probability regions consistent with expected histologic features. Conclusions Tile-level AI modeling enables accurate, interpretable prediction of somatic mutations in mRCC using H&E-stained WSIs. This approach may offer a scalable and accessible tool for expanding molecular profiling in settings without widespread access to NGS.

\"Anyone who has ever seen a Disney movie knows that the iconic images are beautifully conveyed via the magnificent posters. The tone of the movie and the full range of emotions we experience in seeing the film are often captured in a single poster. After having seen and experienced a wonderful Disney motion picture, the mere sight of the poster can bring back the feelings of having taken the journey by watching the film. Disney Movie Posters is a tribute to those posters, which tell the story both before and after we see the movie. Disney Movie Posters have been an important part of the motion picture process since Disney began making motion pictures. Not only are they eye-catching pieces of artwork, they are also designed to entice the movie-going audience. From Steamboat Willie, to Frozen and countless movies in between, Disney Movie Posters have been an important part of the films themselves. Disney shorts, animated movies, live action movies and Pixar movies can be remembered and honored by the posters that so efficiently capture the magic of the film.\"--provided by publisher.

Abstract Background Despite recent advances, metastatic clear cell renal cell carcinoma (ccRCC) remains largely incurable in most patients, and novel immunotherapeutic strategies to address checkpoint inhibitor refractory renal cell carcinoma are needed. Natural killer (NK) cells are immune effector lymphocytes that are specialized in the cytotoxic elimination of cancer cells. Chimeric antigen receptor (CAR) NK cells have also shown promising effects in clinical trials. IL-12 is a potent cytokine that mediates type 1 immunity and antitumor responses but with systemic toxicity. We hypothesize that IL-12 secreted by CD70-CAR NK cells will allow “tumor-directed” IL-12 delivery and with the incorporation of a novel motif, collagen-binding domain A3, we will further minimize toxicity. Methods We engineered lentivectors to express CD70-CAR, CD70-CAR+IL-12, and CD70-CAR+IL-12/A3, and evaluated their transduction efficiencies in human NK cells. The phenotypes of IL-12-secreting CD70-CAR NK cells were analyzed using flow cytometry and bulk RNA sequencing. Untransduced (UTD) and modified NK cells were cocultured with ccRCC tumor cell lines (A498 and ACHN) at various effector to target (E: T) ratios to assess target cell lysis. NK cell activation was determined by measuring degranulation (CD107a) and IFNγ expression. IFNγ secretion was quantified from coculture supernatants. The killing of ccRCC PDXs was similarly evaluated. In vivo, the therapeutic efficacy of CD70-CAR+IL-12/A3 NK cells was tested using ccRCC xenograft models using A498 cells injected subcutaneously into NSG mice. The mice were divided into five groups: no treatment (PBS), NK cell, CD70-CAR NK cell, CD70-CAR+IL-12 NK cell, and CD70-CAR+IL-12/A3 NK cell. When tumors reached ∼100 mm³, 1x10^6 NK cells were administered intravenously. Tumor volumes and mouse survival were monitored. For safety evaluation, the animals were closely monitored for their weight and wellbeing and plasma collected on day 7 post CAR NK cell injection to evaluate the production of IL-12 and other key inflammatory cytokines including IL-1β, IL-2, IL-6, IFNγ, IL-18 and GM-CSF that are associated with cytokine release syndrome (CRS). Results High transduction efficiency was achieved in the NK cells with all three CAR constructs (50–85%). IL-12-engineered CD70-CAR NK cells exhibited significantly increased surface expression of CD25, LFA1, CXCR4, and sLex compared to regular CD70-CAR NK cells. Gene expression analysis revealed upregulation of IL12A, IL12B, IFNG, GZMB, IRF1, SOCS3, and ABCA1, alongside downregulation of CISH. These cells also displayed enhanced metabolic fitness, with an increased oxygen consumption rate (OCAR). CD70-CAR NK cells that secrete IL-12 and IL-12/A3 exhibited significantly increased cytotoxicity in vitro against ccRCC tumor cell lines A498 and ACHN, as well as CD70+ ccRCC patient-derived xenografts (PDXs). The presence of IL-12 and IL-12/A3 effectively stimulated NK cell degranulation and IFNγ production following coculture with ccRCC tumor cells. In vivo studies showed that CD70-CAR NK cells secreting IL-12 and IL-12/A3 achieved notably better control of ccRCC tumors compared to CD70-CAR NK cells alone. Mice treated with CD70-CAR+IL-12/A3 NK cells demonstrated better survival rates than those treated with CD70-CAR+IL-12 NK cells or other constructs (Fig. 1). Additionally, CD70-CAR+IL-12/A3 NK cells resulted in significantly lower systemic levels of IL-12 7 days after CAR NK cell infusion compared to CD70-CAR+IL-12 NK cells, suggesting that fusing IL-12 to a collagen binding domain can reduce systemic IL-12 exposure. Conclusions Incorporating IL-12/A3 into CAR NK cells is feasible, safe, and significantly enhances their cytotoxicity against ccRCC tumor cells in vitro and in vivo. These findings provide strong rationale for further clinical evaluation of CD70-CAR+IL-12/A3 NK cells in patients with advanced ccRCC.

In 'Posters: A global history' Elizabeth Guffey tells the story of this ephemeral art form, from its birth in the nineteenth century to its place in contemporary culture. She argues that even among today's burgeoning digital media, few forms of graphic design can rival posters for their tangibility and sheer spatial presence. From London to Ramallah, Los Angeles to Lagos, posters provide new opportunities to communicate across public spaces that are themselves increasingly transformed by digital media. This book re-examines the roots of the poster, charting its rise from the revolutionary lithographs that papered nineteenth-century London and Paris to twentieth-century works of propaganda, advertising, pop culture and protest. It considers the lives of posters: where and why posters were made, and why and how they endured. It examines posters from today's world, including posters of Palestinian martyrs and West African examples describing voodoo activities, and offers a rich variety of both familiar and lesser-known examples from the Soviet Union, China, Eastern and Western Europe, the U.S. and elsewhere. Beautifully illustrated, Posters provides a fresh history of the nineteenth- and twentieth-century poster as well as revealing insights into the designs and creative practices of our twenty-first-century world.

Abstract Background Tivo is a potent and highly selective VEGFR inhibitor designed to optimize VEGF blockade and minimize off-target toxicities. In TiNivo-2, patients with mRCC who had previous exposure to ICI, were randomized to receive study treatment as 2 L or 3 L with Tivo alone at 1.34 mg, or at 0.89 mg in combination with the ICI nivolumab (nivo).[1] The addition of nivo to tivo in second line (2 L) or third-line treatment (3 L) did not improve outcomes, and tivo monotherapy showed activity as a 2 L treatment in the post ICI setting. In TIVO-3, randomized patients had at least two previous systemic treatments and received tivo or sorafenib. We carried out a safety review of tivozanib monotherapy in these 2 randomized trials in the context of populations that had been previously exposed to VEGFR-TKI and ICI treatment. Methods The safety profile of tivo monotherapy was evaluated in these two phase 3 trial cohorts that consisted of the tivo monotherapy arms of TiNivo-2 (N = 171), and TIVO-3 (N = 173).[2] Results Patient baseline characteristics of the two tivo monotherapy cohorts showed some differences, most notably in the distribution of previous exposure to VEGFR target therapy and ICIs: in TIVO-3, exposure to two prior VEGFR-TKI was 45%, to prior ICI plus VEGFR-TKI was 27%, and to a prior VEGFR-TKI plus other agent was 28%. Whereas inTiNivo-2, exposure to prior ICI was 100% (71% as the most recent line of therapy), while exposure to VEGFR-TKI was: none 31%, one 56% and two 13%. Additionally, 94% of TIVO-3 participants were white, compared with 62% of those in TiNivo-2. The incidence of grade 3-4 TEAEs and serious AEs was lower in TiNivo-2, however there was consistency in the incidence of any cause TEAEs, as well as those leading to death or treatment modifications in both cohorts (Table 1). For TEAEs ≥Grade 3, hypertension was the most common, occurring in approximately 20% of patients in each cohort; while the incidence of all other TEAEs ≥Grade 3 was lower, they also occurred at similar rates in each cohort (Table 1). Conclusions Here, results show that tivo has a manageable safety profile across phase 3 trials. The better tolerability of tivo in the TiNivo-2 study vs TIVO-3 is driven in part by more patients enrolled in the earlier lines of treatment (2 L).1. Choueiri et al. Lancet 20242. Rini et al. Lancet Oncol 2020