◥Purpose: Intratumoral immunosuppression mediated by myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) represents a potential mechanism of immune checkpoint inhibitor (ICI) resistance in solid tumors. By promoting TAM and MDSC infiltration, IL1b may drive adaptive and innate immune resistance in renal cell carcinoma (RCC) and in other tumor types.Experimental Design: Using the RENCA model of RCC, we evaluated clinically relevant combinations of anti-IL1b plus either anti-PD-1 or the multitargeted tyrosine kinase inhibitor (TKI), cabozantinib. We performed comprehensive immune profiling of established RENCA tumors via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA sequencing (RNA-seq). Similar analyses were extended to the MC38 tumor model.Results: Analyses via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA-seq showed that anti-IL1b reduces infiltration of polymorphonuclear MDSCs and TAMs. Combination treatment with anti-IL1b plus anti-PD-1 or cabozantinib showed increased antitumor activity that was associated with decreases in immunosuppressive MDSCs and increases in M1-like TAMs.Conclusions: Single-cell RNA-seq analyses show that IL1b blockade and ICI or TKI remodel the myeloid compartment through nonredundant, relatively T-cell-independent mechanisms. IL1b is an upstream mediator of adaptive myeloid resistance and represents a potential target for kidney cancer immunotherapy.
OBJECTIVES-Alpha-methylacyl-CoA racemase (AMACR) has been used as a diagnostic biomarker for prostate cancer (CaP) and is now a standard biomarker for needle biopsy specimens with ambiguous lesions. In this study, we evaluate the possibility of using AMACR variants to improve the specificity of CaP detection. METHODS-We used in silico analysis and molecular cloning to discover new AMACR variants and quantitative RT-PCR to measure the transcript levels of AMACR and its variants in four prostate cell lines and 23 pairs of CaP and adjacent normal tissue.RESULTS-We found four novel variants, IAs, IBL, IBLd, and IBLi. Transcript levels of the majority of AMACR variants were significantly upregulated in CaP as compared with its adjacent normal counterparts. A variants, the functional variants based on bioinformatic analysis, showed levels of transcript expression in CaP in this order: IA≫IAd=IIA≫IIAs>IAs. In contrast, the expression of the B variants, which appear to be nonfunctional due to the absence of exon 3, was lower than that of the A variants. IB was the most abundant form of B variant; and expression of IIB was negligible. More important, the difference between levels of variant IA, IAd, IIA, IIAs, IB, and IBLi in CaP and normal tissue was significantly higher than the difference in levels of total AMACR. CONCLUSIONS-Our data suggest that AMACR variants have better power than total AMACR in discriminating between CaP and adjacent normal tissue. These findings may be useful for the development of future diagnostic assays.
Background: Growing evidence suggests a possible sex disparity in COVID-19 disease related outcomes. Objective: To explore the sex disparity in COVID-19 cases and outcomes using New York City (NYC) population level data. Setting: NYC surveillance data from February 29 to June 12, 2020. Participants: Individuals tested for COVID-19 in metropolitan NYC. Outcome Measurements and Statistical Analysis: Outcomes of interest included rates of COVID-19 case positivity, hospitalization and death. Relative risks and case fatality rates were computed for all outcomes based on sex and were stratified by age groups. Results and Limitations: 911,310 individuals were included, of whom 434,273 (47.65%) were male and 477,037 (52.35%) were female. Men represented the majority of positive cases (n=106,275, 51.36%), a majority of hospitalizations (n=29,847, 56.44%), and a majority of deaths (n=13,054, 59.23%). Following population level adjustments for age and sex, testing rates of men and women were equivalent. The majority of positive cases and hospitalizations occurred in men for all age groups except age >75 years, and death was more likely in men of all age groups. Men were at a statistically significant greater relative risk of case positivity, hospitalization, and death across all age groups except those <18 years of age. The most significant difference for case positivity was observed in the 65-74 age group (RR 1.22, 95%CI 1.19-1.24), for hospitalization in the 45-65 age group (RR 1.85, 95% 1.80-1.90), and for death in the 18-44 age group (RR 3.30, 95% CI 2.82-3.87). Case fatality rates were greater for men in all age-matched comparisons to women. Limitations include the use of an evolving surveillance data set and absence of further demographic characteristics such as ethnographic data. Conclusion: Men have higher rates of COVID-19 positivity, hospitalization, and death despite greater testing of women; this trend remains after stratification by age.
Mitochondria provide the first line of defense against the tumor-promoting effects of oxidative stress. Here we show that the prostate-specific homeoprotein NKX3.1 suppresses prostate cancer initiation by protecting mitochondria from oxidative stress. Integrating analyses of genetically engineered mouse models, human prostate cancer cells, and human prostate cancer organotypic cultures, we find that, in response to oxidative stress, NKX3.1 is imported to mitochondria via the chaperone protein HSPA9, where it regulates transcription of mitochondrial-encoded electron transport chain (ETC) genes, thereby restoring oxidative phosphorylation and preventing cancer initiation. Germline polymorphisms of NKX3.1 associated with increased cancer risk fail to protect from oxidative stress or suppress tumorigenicity. Low expression levels of NKX3.1 combined with low expression of mitochondrial ETC genes are associated with adverse clinical outcome, whereas high levels of mitochondrial NKX3.1 protein are associated with favorable outcome. This work reveals an extranuclear role for NKX3.1 in suppression of prostate cancer by protecting mitochondrial function. Significance: Our findings uncover a nonnuclear function for NKX3.1 that is a key mechanism for suppression of prostate cancer. Analyses of the expression levels and subcellular localization of NKX3.1 in patients at risk of cancer progression may improve risk assessment in a precision prevention paradigm, particularly for men undergoing active surveillance. See related commentary by Finch and Baena, p. 2132. This article is highlighted in the In This Issue feature, p. 2113
Primary Clear Cell Renal Carcinoma (ccRCC) is a highly heterogenous disease with a variable disease course post-surgery, and ccRCC tumor micro-environment has thus far not been characterized at the single-cell level with the whole-transcriptome resolution enabled by single-cell RNA Sequencing (scRNASeq). To elucidate the cellular and transcriptional mechanisms driving disease recurrence, we performed scRNASeq on both hematopoietic and non-hematopoietic populations from tumor and tumor-adjacent tissue from primary resections of treatment-naïve ccRCC patients (n=11), thus producing a complete atlas of the ccRCC tumor microenvironment. Furthermore, in order to mitigate gene dropout inherent to scRNASeq and commonly preventing detection of >80% of genes, we leveraged the VIPER algorithm, which quantitates protein activity, to infer the proteomic regulators of cell state. Clustering at the gene expression level enabled construction of lineage-specific gene regulatory networks applying ARACNe, the Algorithm for Reconstruction of Accurate Cellular Networks, from which protein activity of upstream regulatory molecules could be inferred by VIPER. Comparison with protein-level expression data from antibody-based, high-parameter spectral flow cytometry in the same patients shows that VIPER-measured protein activity systematically abrogated gene dropout effects on a repertoire of >6,000 regulatory proteins, comparing favorably with antibody-based measurements. This helped comprehensively characterize the individual cellular sub-populations comprising the ccRCC tumor and peri-tumor microenvironment, as well as their specific master regulators and candidate cell-cell interactions, revealing several populations undetectable by gene expression analysis. Specifically, we uncovered a novel tumor-specific, macrophage subpopulation characterized by significant upregulation of TREM2, APOE, and C1Q, as validated by spatially-resolved, quantitative multispectral immunofluorescence (qmIF). These tumor-specific macrophages were statistically significantly over-represented in a separate validation cohort of patients who recurred following surgery (n=4) compared to patients who did not recur (n=4). This study highlights the substantial resolution increase afforded by VIPER and identifies TREM2/APOE/C1Q-positive macrophage infiltration as a potential biomarker for ccRCC recurrence and a candidate target for intervention. Furthermore, it provides a highly-generalizable methodology to study the role of rare subpopulations by leveraging VIPER on scRNASeq data. Citation Format: Aleksandar Obradovic, Nivedita Showdhury, Casey Ager, Vinson Wang, Lukas Vlahos, Xinzheng V. Guo, David H. Aggen, James McKiernan, Andrea Califano, Charles G. Drake. Tumor-specific cell populations in clear cell renal carcinoma associated with clinical outcome identified using single-cell protein activity inference [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-024.
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