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Milton Glaser has designed more than 500 posters. Some, like his 1967 Bob Dylan poster for Columbia Records, are icons; others, like the series celebrating \"I [heart] New York,\" evoke his best-known works. Milton Glaser Posters includes more than 400 of them, with Glaser's own commentary describing his intentions and inspiration. It is a delight for the art lover, an education in visual storytelling, and a journey through the cultural life of half a century, all rolled into one compact, intense book.

Abstract Background With immune checkpoint inhibitors (ICIs) now widely used as a primary treatment for metastatic RCC, understanding the composition and function of the tumor microenvironment (TME) has become more important. Numerous studies have focused on T cells to explain both treatment response and resistance, and single-cell RNA sequencing (scRNA-seq) has revealed the complex heterogeneity of T cell states. However, the contribution of myeloid cells (particularly tumor-associated macrophages (TAMs), which are known to suppress antitumor immunity) remains incompletely understood in the context of ICI therapy. In this study, we aimed to investigate TAM populations associated with ICI resistance in RCC using single-cell transcriptomic profiling. Methods We analyzed 70 tumor samples (58 clear cell and 12 non-clear cell) obtained from 63 patients with advanced RCC. The cohort included 9 untreated patients, 10 who received non-ICI systemic therapies, and 44 who were treated with ICI-based regimens. From the ICI-based therapy group, we excluded 17 patients who had stable disease and focused on 29 tumor samples from 27 patients with either pre-treatment (n = 15) or post-treatment (n = 14) samples. These patients received various ICI regimens, including mono-ICI (n = 11), ICI plus ICI (n = 11), ICI plus VEGF inhibitor (n = 6), and ICI plus IDO1 inhibitor (n = 1). We performed scRNA-seq (10x Genomics) on all samples and applied non-negative matrix factorization (NMF) to identify transcriptional programs within TAMs. We then compared these programs between responders (n = 18, complete or partial response) and non-responders (n = 11, progressive disease) based on RECIST criteria. Statistical significance was assessed using the Wilcoxon signed-rank test. Results A total of 443 337 high-quality viable cells were analyzed and classified into major cell types, including lymphoid, myeloid, tumor, endothelial, and fibroblast compartments. Within the TAM compartment, NMF uncovered 8 gene expression programs, such as “antigen presentation”, “S100A8/9 inflammation”, “stress response”, “C1Q/APOE/TREM2 signaling”, “CD163/MRC1-M2-like”, “hypoxia-related signaling”, “interferon-stimulated response”, and a distinct “LILRB/SIGLEC10” immunosuppressive program. This LILRB/SIGLEC10-enriched TAM subcluster was significantly more abundant in non-responders than in responders (P = .005). Importantly, this difference was also observed in pre-treatment samples alone (P = .014), suggesting it may be involved in primary resistance. These TAMs expressed higher expression levels of immunosuppressive LILRB1/2/3 genes, the inhibitory receptor SIGLEC10 (a recently characterized “don’t eat me” signal), and the immune checkpoint molecule VISTA, compared to other TAM subclusters (p < 2.22E-16 for each gene). Conclusions Our scRNA-seq-based analysis identified a distinct population of TAMs characterized by immunosuppressive transcriptional programs associated with poor response to ICI therapy in RCC. These findings provide insight into potential mechanisms of resistance and suggest that targeting this TAM subset may improve therapeutic efficacy. This study also demonstrates the utility of single-cell transcriptomics for uncovering key immunoregulatory populations in large clinical cohorts.

Abstract Background Clear cell renal cell carcinoma (ccRCC), a metabolic disease originating from renal proximal convoluted tubule (PCT) epithelial cells, remains incompletely understood regarding its initiating signaling events. Methods We use clinical data-driven analysis, combined with pathological validations to identify γ-butyrobetaine hydroxylase 1 (BBOX1), a key enzyme in carnitine synthesis predominantly expressed in PCT cells, as a tumor suppressor in ccRCC. We also conducted substantial in vitro and in vivo functional studies to understand the role of BBOX1 in ccRCC tumorigenesis. In terms of mechanistic studies, we combined a variety of methods, including transcriptomics, metabolomics, and IP-mass spectrometry, to uncover the underlying mechanisms of BBOX1 in regulating metabolism and ccRCC development. Results BBOX1 expression is lost during ccRCC malignant transformation, and its restoration reduces cell viability in physiological medium and inhibits xenograft tumor growth. Transcriptomic analyses reveal that BBOX1 suppresses critical metabolic pathways, including mTORC1 signaling and glycolysis in ccRCC. Further, we identify TANK-binding kinase 1 (TBK1) as an essential mediator of mTORC1 and glycolysis activation and as a target of BBOX1-mediated tumor suppression. Mechanistically, BBOX1 disrupts TBK1 activation by preventing its interaction with the upstream activator doublecortin-like kinase 2 (DCLK2). In a therapeutic approach, we developed a novel TBK1 Proteolysis-targeting chimera (PROTAC) to target ccRCC tumorigenesis. Conclusions This BBOX1-TBK1-mTORC1 axis unveils a previously uncharacterized mechanism in ccRCC metabolic dysregulation and highlights potential therapeutic strategies.

A blend of graphic design, bold art or photography & psychology, election posters are an unsung art form, stretching back to the dawn of the 20th century. Exploiting the Conservative Party Archive held at the Bodleian Library which contains over 700 posters, this text charts the evolution of the Conservatives' election posters.

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.

London Transport's poster collection represents the most complete graphic archive of its kind to be assembled by a single organisation over such a long period anywhere in the world. This book is richly illustrated with examples of posters from all periods.

Abstract Background Unlike other cancer types the determinants of anti-PD-1 response in clear cell RCC are not well defined; ccRCC exhibits a low mutational burden and CD8+ T cells infiltration is associated with worse prognosis. Cytomegalovirus (CMV) and human papillomavirus (HPV) infections are postulated to modulate the anti-tumor immune responses within the tumor microenvironment. We sought to investigate the clinical and immunologic impact of CMV and HPV viral transcriptomic signatures, as defined by prior studies, in patients with RCC. Methods RNA-seq data from three RCC prospetive trials were upper-quartile normalized, log2-transformed (TPM + 1), and batch-corrected using ComBat. Transcriptomic scores for CMV (75 genes) and HPV (79 genes) were computed using geometric means (71 and 77 genes were found, respectively). CD8 immunofluorescence (IF) was performed on tumor samples. Overall survival (OS) and progression-free survival (PFS) were assessed using multivariable Cox regression, adjusting for age at therapy start, gender, IMDC risk, sarcomatoid/rhabdoid features, and number of previous lines received. Results A high intratumoral CMV transcriptomic score was significantly correlated with T-effector signature (ρ  =  0.54, p = 4.8 × 10−6), IF tumor core CD8+ (ρ  =  0.43, P < .001), IF tumor margin CD8+ (ρ  =  0.41, P < .001), and myeloid signature (ρ  =  0.40, P < .001). The CMV score was significantly higher in infiltrated versus excluded/desert tumors (P = .0079). The CMV score was associated with worse OS among patients receiving immune checkpoint blockade (ICB) (HR 4.98, P = .039). In contrast, the HPV transcriptomic score showed only a modest correlation with myeloid signature (ρ  =  0.24, P = .051) and no association was found with OS nor PFS. Conclusions In metastatic RCC, a high tumor CMV transcriptomic score was associated with a paradoxical immune landscape, marked by CD8+ infiltration yet co-enriched with suppressive myeloid signatures, that predicts inferior overall survival following ICB. These viral signatures within the complex immune architecture of RCC may help understand immune responsiveness and resistance within distinct genomic and therapeutic contexts.

Abstract Background Cabozantinib, a tyrosine kinase inhibitor (TKI) that targets multiple kinases, including vascular endothelial growth factor receptor, is a preferred treatment option for patients with previously treated advanced renal cell carcinoma (RCC); however, its effectiveness after treatment with first-line immuno-oncology (IO)-based combinations is not fully understood. The efficacy and safety of second-line cabozantinib, with or without atezolizumab, were evaluated in the multicenter, randomized, phase 3 CONTACT-03 study (Pal et al., Lancet 2023; ClinicalTrials.gov: NCT04338269). Here, we report the results of a post hoc analysis of patients from CONTACT-03 who received contemporary IO–IO or IO–TKI combination regimens in the first-line setting. Methods In CONTACT-03, adults with metastatic RCC and disease progression on or after IO-based regimens were randomized to oral cabozantinib 60 mg once daily alone or with atezolizumab 1200 mg intravenously every 3 weeks. The current analysis evaluated progression-free survival (PFS) by blinded independent central review (BICR), overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety in the subgroup of patients who received first-line standard-of-care IO–IO (ipilimumab–nivolumab) or IO–TKI (avelumab–axitinib, pembrolizumab–axitinib, or pembrolizumab–lenvatinib) combinations prior to enrolling in CONTACT-03. Results Of 522 patients enrolled in CONTACT-03, 107 and 129 in the cabozantinib and cabozantinib plus atezolizumab arms, respectively, received prior treatment with first-line IO–IO or IO–TKI combinations. Efficacy outcomes were comparable between treatments. For cabozantinib and cabozantinib plus atezolizumab, respectively, median PFS by BICR was 10.4 months (95% confidence interval [CI], 7.95–12.45) and 10.2 months (95% CI, 8.34–10.64), and median OS was not estimable (NE; 95% CI, 18.30–NE) and 24.3 months (95% CI, 20.24–NE). The ORR was 36% with cabozantinib and 37% with cabozantinib plus atezolizumab (all partial responses); 50% and 52% of patients had a best response of stable disease, and 10% and 5% had progressive disease, respectively. The median DOR was 15.1 months (95% CI, 10.28–NE) with cabozantinib and 10.5 months (95% CI, 7.95–NE) with cabozantinib plus atezolizumab. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 48% of patients treated with cabozantinib and in 58% of those treated with cabozantinib plus atezolizumab; serious TRAEs were reported in 13% and 25% of patients, respectively. Dose modifications due to adverse events were reported in 87% of patients treated with cabozantinib and in 92% of those treated with cabozantinib plus atezolizumab; discontinuation of treatment due to adverse events occurred in 5% and 17% of patients, respectively. Conclusions From this post hoc subgroup analysis of CONTACT-03 can help inform treatment decisions for patients with disease progression on first-line IO-containing combinations. The data suggest that second-line cabozantinib is effective in patients with advanced RCC previously treated with contemporary first-line IO–IO or IO–TKI regimens. Safety outcomes were consistent with the overall study population.

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.