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  • American Association for Cancer Research (AACR)  (41)
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  • 1
    Online Resource
    Online Resource
    Abstract P5-02-03: Highly multiplexed tissue-based cyclic immunofluorescence in breast cancer for precision oncology
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P5-02-03-P5-02-03
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P5-02-03-P5-02-03
    Abstract: Background: Tissue-based cyclic immunofluorescence (t-CyCIF) is a recently described technique for highly multiplexed immunofluorescence microscopy of formalin-fixed, paraffin-embedded (FFPE) specimens. Via an iterative process, successive four-channel images are collected from the same sample and then registered to each other to generate a high-dimensional representation that is used for visualization and analysis. This technique can be used to capture up to 60 different antigens on a single FFPE tumor section and permits quantification of cell lineage and state markers, intracellular signaling proteins, drug targets and immune cell antigens, thereby promoting biomarker discovery efforts that are fundamental to precision oncology. As with most technologies that utilize immunostaining, proper antibody validation is key to reliable performance. In this study we used t-CyCIF to evaluate multiple antibodies directed against proteins commonly used to characterize breast carcinomas and their associated microenvironment. Our goal was to validate these antibodies on the t-CyCIF platform prior to the more widespread use of this technology to propel novel discoveries on breast cancer initiation, progression and treatment. Methods: To choose the optimal antibody candidate for each biomarker in t-CyCIF, we compared multiple fluorophore-conjugated antibodies for each of the following three proteins routinely evaluated in breast carcinomas: estrogen receptor (ER), progesterone receptor (PR) and HER2. For each of these, a single antibody commonly used in clinical practice was used as a reference. Analyses were performed at the level of pixels, cells and tissue cores. In addition, inter-assay analyses were performed comparing: (1) t-CyCIF vs. immunohistochemistry (IHC), the latter assessed both by digital pathology and by two independent pathologists; and (2) t-CyCIF vs. fluorescence in situ hybridization (FISH) for HER2. Following validation of these antibodies, we evaluated the expression of CD45, CD68, PD-L1, p53, Ki67 and androgen receptor along with ER, PR and HER2, to better understand both the tumor microenvironment and the cell identities/states in breast carcinomas. Results: A total of 948 tissue cores were included in the study. In the first phase, 13 different antibodies were analyzed: three raised against ER and five each against PR and HER2. The pixel-to-pixel evaluation resulted in r scores using Pearson correlation equal to 0.86 for both ER markers tested; ranging from 0.88 to 0.93 for PR; and from 0.56 to 0.94 for HER2. The correlation scores in single-cell comparisons ranged from 0.76 to 0.88 for ER, 0.54 to 0.81 for PR, and from 0.56 to 0.76 for HER2. Comparisons were then performed at the tissue core level. In light of the data generated through these multiple levels of analyses, we identified fluorophore-conjugated candidates for use in t-CyCIF. Correlation scores on the tissue core level were high in the inter-assay analyses, i.e. t-CyCIF vs. IHC (e.g. r scores up to 0.91 for HER2 on t-CyCIF vs. IHC) and t-CyCIF vs. HER2 FISH (r scores up to 0.71). In the second phase, we characterized the tumor microenvironment and cell identities present in 260 breast carcinomas. With a qualified panel of antibodies, we performed single-cell analyses of 589,343 cells and identified unexpected patterns of PD-L1 expression in distinct populations of tumor cells. Conclusion: This study is the first to evaluate the performance of breast cancer-specific antibodies in a highly multiplexed imaging platform such as t-CyCIF. This work demonstrates a step-by-step approach for qualifying reagents to be used in a multiplexed, spatially resolved tissue imaging modality. This validation study will facilitate the use of t-CyCIF for additional studies in breast cancer to evaluate both tumor elements and components of the microenvironment. Citation Format: Ricardo G Pastorello, Jia-Ren Lin, Ziming Du, Shaolin Mei, Krishan Taneja, Deborah A Dillon, Stuart J Schnitt, Peter K Sorger, Elizabeth A Mittendorf, Sandro Santagata, Jennifer L Guerriero. Highly multiplexed tissue-based cyclic immunofluorescence in breast cancer for precision oncology [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-02-03.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P5-02-03
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 2
    Online Resource
    Online Resource
    Abstract P4-06-09: Pick-Seq®: Multi-parameter imaging combined with RNA sequencing of tissue section micro-regions for spatial analysis in breast carcinoma
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P4-06-09-P4-06-09
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P4-06-09-P4-06-09
    Abstract: Multi-parameter tissue imaging allows for a contextual understanding of tumor cells in relation to the tumor microenvironment. Pick-Seq is a novel workflow uniquely enabled by the RareCyte CyteFinder® Instrument that combines interrogation of multiple protein markers with investigation of gene expression from selected micro-regions on tissue slides. In this study, formalin-fixed, paraffin-embedded tonsil sections and OCT-embedded, frozen breast cancer sections were stained with epithelial and lymphocyte markers by multi-parameter immunofluorescence (IF) and scanned with the CyteFinder Instrument to identify regions of interest. Based on IF staining patterns, 40 μm diameter micro-regions were retrieved with the integrated CytePicker® Retrieval Module. Micro-region RNA was isolated for whole transcriptome amplification, library preparation, and sequencing. Resulting data were analyzed for differential gene expression, cell composition, and T cell receptor (TCR) sequences. Transcriptomic analysis of tonsil micro-regions confirmed increased expression of B cell markers in follicles and T cell markers in the T cell zone. CIBERSORT revealed distinct cellular compositions between T cell zones and the B cell follicles. Principle component analysis of gene expression found that micro-regions retrieved from the two follicles clustered independently from each other, and from the T cell zone micro-regions. Fragments per kilobase million (FPKM) analysis revealed differing expression of genes, particularly CD19 and CD21, between the adjacent follicles. Subsequent staining confirmed differential protein expression, indicating that only one follicle contained a germinal center. In breast carcinoma, regions were identified for CytePicker retrieval that included (1) tumor cells, (2) tumor cells with interspersed tumor infiltrating lymphocytes (TIL), or (3) adjacent lymphoid aggregates. CIBERSORT analysis demonstrated the presence of T cell-associated transcriptomic profiles in lymphoid aggregates and in TIL-containing micro-regions that were proportional to the number of T cells retrieved. Aligned RNA-seq reads were further analyzed to identify TCR α and β chain sequences from retrieved TILs. These data establish the potential of combining multi-parameter IF microscopy with deep RNA sequencing as a powerful tool for investigation and biomarker discovery in the immuno-oncology of breast cancer. Citation Format: Nolan Ericson, Rebecca Podyminogin, Jennifer Chow, Jia-Ren Lin, Yu-An Chen, Zoltan Maliga, Peter Sorger, Kyla Teplitz, Eric Kaldjian, Tad George. Pick-Seq®: Multi-parameter imaging combined with RNA sequencing of tissue section micro-regions for spatial analysis in breast carcinoma [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-06-09.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P4-06-09
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
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    Abstract 122: Highly multiplexed, spatially-resolved tissue imaging of genetically engineered mouse models of cancer to discover and characterize immune regulators of tumorigenesis
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 122-122
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 122-122
    Abstract: Despite the encouraging success of immunotherapy for certain malignancies, most patients with solid tumors do not yet benefit from such therapies. It is therefore critical that we identify factors dictating responsiveness to immunotherapy by more completely characterizing tumor-immune interactions. Even though immunotherapies are used in humans, in-depth analysis of murine models is essential for a mechanistic understanding of the crosstalk among tumor, immune, and stromal components of the tumor microenvironment (TME): only animal models have the necessary manipulability and reproducibility for causal, mechanistic studies. However, murine modelling must be combined with spatially resolved analytical methods such as highly multiplexed tissue imaging that enable accurate characterization of the TME at a single-cell level. Here we use tissue cyclic immunofluorescence (t-CyCIF) multiplexed imaging to characterize the immune microenvironment of a mouse lung adenocarcinoma model initiated via lentiviral delivery of Cre recombinase into the lungs of KrasLSL-G12D/+;p53fl/fl (KP) mice. Using this new platform, we identify tumor cells and immune cell types (dendritic cells, NK cells, macrophages, B cells, helper T cells, regulator T cells and cytotoxic T cells). We characterize the effects of expressing tumor antigen (i.e., LucOS), of CRISPRa based upregulation of the chemokines (e.g., CXCL10), and of combination immune check point inhibitor treatments (e.g., one-week treatment with anti-PD-1 and anti-CTLA-4 (PC)). Remarkably the total immune composition of the mouse lungs remains relatively unchanged following these perturbations, but there are marked changes in the immune cell localization in tumor nodules, in the number and size of immune cell networks and in the functional activation states of cytotoxic T cells. For example, one week of PC treatment did not affect tumor burden and did not change the extent of immune cell infiltration however, it did drastically change cytotoxic T cell phenotypes with increased effector phenotypes (i.e., GzmB and Perforin expression and proliferation) and decreased exhaustion-like phenotypes (i.e., PD-1 and Tim-3 expression). Lymphocyte networks decreased in number but were closer to tumors. Using high-dimensional protein expression data to characterize GEMM models following in situ genetic or therapeutic perturbation is a powerful new platform to investigate tumor-immune interactions. Citation Format: Giorgio Gaglia, Megan Burger, Claire Ritch, Danae Argyropoulou, Yang Dai, Shannon Coy, Jia-Ren Lin, Peter Sorger, Tyler Jacks, Sandro Santagata. Highly multiplexed, spatially-resolved tissue imaging of genetically engineered mouse models of cancer to discover and characterize immune regulators of tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 122.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-122
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 4
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    Abstract 1816: Phenogenomic characterization of immunomodulatory purinergic signaling in glioblastoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1816-1816
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1816-1816
    Abstract: INTRODUCTION: Extracellular purinergic signaling plays critical roles in the regulation of tumor growth and anti-tumor immunity via autocrine/paracrine binding of metabolites to receptors on neoplastic and non-neoplastic populations. Extracellular purine concentrations are principally mediated by the ectonucleotidase enzymes CD39 and CD73, which catabolize ATP to adenosine. Within the tumor microenvironment, neoplastic, immune, and stromal cells expressing these enzymes may co-localize to generate an immunosuppressive adenosine-rich niche. However, the cellular composition, spatial architecture and phenotypic properties of these tumor ecosystems and their relationship to tumor genotype have been poorly characterized. METHODS: We quantified CD73 expression by immunohistochemistry (IHC) in a cohort of CNS tumors [meningiomas(N=222), gliomas(N=244), ependymomas(N=44), medulloblastomas(N=24), craniopharyngiomas(N=38)]. We used publicly-available single-cell RNA-seq data and 36 marker multiplexed tissue imaging (t-CyCIF) of 139 clinically and genomically annotated glioblastomas to characterize CD39 and CD73 expressing populations, define immune architecture and tumor cell states at single cell resolution, evaluate spatial correlations, and identify markers of clinical outcome. Mass spectrometry imaging (MALDI-MSI) was employed to generate spatially-resolved quantification of purine metabolite levels in glioblastoma resections (N=9). RESULTS: IHC revealed strong CD73 expression in meningiomas and gliomas. Tumor CD73 expression was associated with poor progression-free-survival in IDH-wildtype glioblastoma (p=0.04). scRNA-seq in glioblastoma revealed that CD73 is predominantly expressed by tumor cell populations, while CD39 is predominantly expressed by monocytic (macrophage, microglial) populations. t-CyCIF showed enrichment of EGFR, Ki-67, and TP53 expression in CD73-high tumor cells at a single cell level independent of genotype, as well as significant spatial correlation between CD73 expression in tumor cells and CD39 expression in macrophages. MALDI-MSI showed significantly greater adenosine concentrations in glioblastomas with high CD73 expression. CD73 expression significantly correlated with EGFR amplification or C-terminal deletion (EGFRvIII or variants), type-II interferon signaling, and PD-L1 expression in glioblastoma. CONCLUSIONS: Phenogenomic analysis of purinergic signaling in glioblastoma revealed correlations between CD73 expression and genotype, adenosine concentration, and clinical outcome. Spatial analysis revealed interaction between macrophages CD39 expression and tumor cell CD73 expression, suggesting that these populations may interact to suppress anti-tumor immunity. Anti-CD73 therapy may provide therapeutic benefits in glioblastoma by blunting immunosuppressive and oncogenic adenosine signaling. Citation Format: Shannon Coy, Jia-Ren Lin, Shu Wang, Sylwia Stopka, Rumana Rashid, Jaeho Hwang, Prasidda Khadka, Philipp Euskirchen, Pratiti Bandopadhayay, Patrick Y. Wen, Peter K. Sorger, Nathalie Agar, Keith L. Ligon, Mehdi Touat, Sandro Santagata. Phenogenomic characterization of immunomodulatory purinergic signaling in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1816.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1816
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 5
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    Abstract P2-07-13: High-dimensional, single-cell analysis and transcriptional profiling reveal novel correlatives of response to PARP inhibition plus PD-1 blockade in triple-negative breast cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. P2-07-13-P2-07-13
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P2-07-13-P2-07-13
    Abstract: Background: TOPACIO was a phase I/II study evaluating the PARP inhibitor (PARPi) niraparib in combination with the anti-PD-1 antibody pembrolizumab in patients with locally advanced and metastatic triple-negative breast cancer (TNBC, n=55) and ovarian cancer irrespective of BRCA mutation status. In the efficacy-evaluable population (n=47) the objective response rate (ORR) was 21% and disease control rate (DCR) 49%. Although activity was greater in patients with BRCA mutations (7/15, ORR=47% and 12/15, DCR=80%), durable clinical benefit was seen in patients with wild-type BRCA tumors (3/27, ORR=11% and 9/27, DCR=33%). In a limited cohort of 20 patients with durable clinical benefit, there were 8 BRCA wildtype patients, four of whom had mutations in genes associated with the homologous recombination repair and other DNA damage repair pathways. Pre-treatment tissues were collected and evaluated for tumor PD-L1 status. Patients with PD-L1 positive tumors (28/47, 60%) had a higher response rate (9/28, ORR=32%) than those with PD-L1 negative tumors (1/13, ORR=8%; 6 tumors had unknown PD-L1 status). It remains unstudied whether the tumor’s gene expression profile or immune status in baseline biospecimens is predictive of treatment response. In this study we conducted exploratory biomarker analyses to test the hypothesis that gene expression patterns and immune status are associated with treatment response. Methods: Transcriptional profiling of baseline samples was performed using the BC360 (n=41) and PanCancer IO360 (n=42) panels (Nanostring) and multigene signatures were used to measure tumor and immune activities as well as relative immune cell abundance. Transcriptional analysis was paired with high-dimensional, single-cell cyclic immunofluorescence (CyCIF) of samples that had adequate tissue for analysis (n=19) to characterize the composition and topology of the immune microenvironment at single-cell resolution. Results: Nanostring transcriptional analysis revealed that PAM50 genes stratified tumor samples into 4 subgroups with distinct histology as determined by CyCIF. Each subgroup was capable of responding to niraparib plus pembrolizumab. Multiple genes involved in WNT signaling (WNT5B, TANKS1, TANKS2, PARP4, and NET02) were associated with favorable clinical responses. Low neuropilin and tolloid-like protein 2 (NETO2) gene expression was strongly correlated with favorable progression free survival (PFS; R=-0.61, p=0.0008, Spearman’s correlation), suggesting it may be a predictive biomarker of therapeutic response. Nanostring gene expression signatures for tumor inflammation, apoptosis, and inflammatory chemokines also distinguished responders from non-responders (p & lt;0.05). CyCIF analysis performed on whole tissue sections accounting for 2.97 million single cells revealed 43 distinct cell-states comprising the tumor microenvironment. PD1+CD4+ T cells were significantly correlated with extended PFS (R=0.65, p=0.006, Spearman’s correlation). However, PD1+CD4+ T cells were less abundant in patients who continue to respond to the therapy (2.7-fold reduced, p=0.004), suggesting two groups of responders. Conclusion: WNT signaling, NETO2 and PD1+CD4 T cells are candidate biomarkers for predicting response to niraparib plus pembrolizumab. Further studies are underway to characterize the biological underpinnings of these correlative findings. Citation Format: Jennifer L Guerriero, Gregory J Baker, Jia-Ren Lin, Yu-An Chen, Ricardo Pastorello, Tuulia Vallius, Janae Davis, Clarence Yapp, Sarah E Church, Eric Miller, Anniina Färkkilä, Shaveta Vinayak, Melinda L Telli, Giulia Fulci, Alan D'Andrea, Geoffrey I Shapiro, Sara M Tolaney, Sandro Santagata, Peter K Sorger, Elizabeth A Mittendorf. High-dimensional, single-cell analysis and transcriptional profiling reveal novel correlatives of response to PARP inhibition plus PD-1 blockade in triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-13.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-P2-07-13
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    HAND1 and BARX1 Act as Transcriptional and Anatomic Determinants of Malignancy in Gastrointestinal Stromal Tumor
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 6 ( 2021-03-15), p. 1706-1719
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 6 ( 2021-03-15), p. 1706-1719
    Abstract: Gastrointestinal stromal tumor (GIST) arises from interstitial cells of Cajal (ICC) or their precursors, which are present throughout the gastrointestinal tract. Although gastric GIST is commonly indolent and small intestine GIST more aggressive, a molecular understanding of disease behavior would inform therapy decisions in GIST. Although a core transcription factor (TF) network is conserved across GIST, accessory TFs HAND1 and BARX1 are expressed in a disease state-specific pattern. Here, we characterize two divergent transcriptional programs maintained by HAND1 and BARX1, and evaluate their association with clinical outcomes. Experimental Design: We evaluated RNA sequencing and TF chromatin immunoprecipitation with sequencing in GIST samples and cultured cells for transcriptional programs associated with HAND1 and BARX1. Multiplexed tissue-based cyclic immunofluorescence and IHC evaluated tissue- and cell-level expression of TFs and their association with clinical factors. Results: We show that HAND1 is expressed in aggressive GIST, modulating KIT and core TF expression and supporting proliferative cellular programs. In contrast, BARX1 is expressed in indolent and micro-GISTs. HAND1 and BARX1 expression were superior predictors of relapse-free survival, as compared with standard risk stratification, and they predict progression-free survival on imatinib. Reflecting the developmental origins of accessory TF programs, HAND1 was expressed solely in small intestine ICCs, whereas BARX1 expression was restricted to gastric ICCs. Conclusions: Our results define anatomic and transcriptional determinants of GIST and molecular origins of clinical phenotypes. Assessment of HAND1 and BARX1 expression in GIST may provide prognostic information and improve clinical decisions on the administration of adjuvant therapy.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-3538
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Abstract 6618: Longitudinal, multimodal profiling of metastatic ER+ breast cancer on CDK4/6 inhibitor therapy
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6618-6618
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6618-6618
    Abstract: Introduction: Use of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy has transformed treatment and greatly improved outcome for ER+ breast cancer (BC) patients. However, many BC patients eventually progress on therapy. To understand how ER+ metastatic BC (mBC) tumors become refractory to CDK4/6i, we have created a multimodal, longitudinal tumor atlas to investigate tumor mechanisms of therapeutic resistance, as part of the NCI Cancer Moonshot Human Tumor Atlas Network. By deeply profiling individual patients, we identified a wide variety of putative tumor intrinsic and extrinsic mechanisms of resistance to CDK4/6i. Methods: mBC ER+ patients (n=5) enrolled in the Knight Cancer Institute SMMART Trials program underwent biopsies before treatment and on progression with combination CDK4/6i and endocrine therapy. Biopsies were profiled using: clinical imaging, bulk genomics (WES), transcriptomics (RNAseq), and proteomics (RPPA), multiplex tissue imaging (mIHC, cycIF), single-cell genomics (scDNAseq) and epigenomics (sci-ATAC-seq). Results: Upon progression, patients displayed dysregulated tumor-intrinsic activity via upregulation of gene expression in cell cyclins and kinases as well as genomic copy loss of regulatory factors, such as Rb. On-progression biopsies exhibited increased expression and pathway activity of IL-Jak-Stat and Interferon signaling and changes in tumor microenvironment immune cell composition, including elevated immune cytotoxicity; however, a subset of CD8 T cells expressed LAG3, Tbet, and TIM3, indicating signs of immune activation trending toward exhaustion. Patients also exhibited increased M2 Macrophage and T regulatory cell infiltration, suggesting compensatory feedback to dampen immune activity. Analysis of spatial organization identified cellular neighborhoods recurring across all samples with changes after therapy observed primarily in neighborhoods associated with epithelial-stromal density and immune reactivity/suppression. Conclusion: Findings from this mBC ER+ cohort highlight heterogenous molecular and cellular changes that occur after treatment with a CDK4/6i. We observed multiple tumor intrinsic and extrinsic factors, including modulation of proliferation in neoplastic cells and tumor microenvironment composition, that are suggested to play a role in acquired resistance. We hypothesize a set of patients that initially respond to CDK4/6i therapy may initially display immune activation, but the sustained activation and long-term exposure to therapy may lead to chronic inflammation and immunosuppression. These observations suggest combining CDK4/6i therapy with immunotherapy may provide benefit. We also observed recurrent spatial cellular patterns that recapitulate known biological structures in these tissues; future work will explore association of spatial organization with therapeutic response. Citation Format: Allison L. Creason, Julian Egger, Cameron Watson, Shamilene Sivagnanam, Jia-Ren Lin, Koei Chin, Peter K. Sorger, Lisa M. Coussens, Zahi I. Mitri, Joe W. Gray, Gordon B. Mills, Jeremy Goecks. Longitudinal, multimodal profiling of metastatic ER+ breast cancer on CDK4/6 inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6618.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-6618
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 8
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    Abstract 1705: Slide-based multi-parametric immunophenotyping of human blood samples by cyclic immunofluorescence using the Accucyte-CyteFinder system
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1705-1705
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 1705-1705
    Abstract: Immunophenotyping is an approach to measuring the abundance and functional state of immune cells as a means to understand mechanisms of homeostasis, identify biomarkers of disease, and measure therapeutic and adverse responses to drugs such as immune checkpoint inhibitors. Such studies are conventionally performed using flow cytometry together with combinations of immunomarkers that allow for identification of cell type, maturation state, and activation status. Here we describe a method for profiling circulating human leukocytes with highly-multiplexed immunofluorescence microscopy. The method has distinct advantages over flow cytometry in that it has greater sensitivity for detecting rare cell populations, allows for repeat analysis and long-term storage of precious biological samples, and obviates the requirement for spectral deconvolution. Using an open-source multiplexed immunofluorescence protocol referred to as cyclic immunofluorescence (CycIF), and commercially available reagents and instruments (AccuCyte and CyteFinder; RareCyte Inc.), we show that imaging can provide 16-plex, single-cell intensity data in addition to information on cellular morphology. Analytic technologies borrowed from the field of mass cytometry, such as ViSNE and Phenograph, allow for downstream phenotypic analysis and high-dimensional biomarker discovery. Current efforts now aim to expand the number of validated immune targets and combine imaging with single-cell picking and sequencing technologies. Citation Format: Jia-Ren Lin, Lance U'Ren, Gregory J. Baker, Joshua J. Nordberg, Zoltan Maliga, Jackie L. Stilwell, Eric P. Kaldjian, Peter K. Sorger. Slide-based multi-parametric immunophenotyping of human blood samples by cyclic immunofluorescence using the Accucyte-CyteFinder system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1705. doi:10.1158/1538-7445.AM2017-1705
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-1705
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 9
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    Abstract A082: Single-cell RNA-sequencing of metastatic melanoma identifies a cancer cell-intrinsic program associated with immune checkpoint inhibitor resistance
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Immunology Research Vol. 7, No. 2_Supplement ( 2019-02-01), p. A082-A082
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 7, No. 2_Supplement ( 2019-02-01), p. A082-A082
    Abstract: Immune checkpoint inhibitors (ICI) produce durable responses in some melanoma patients, but many patients derive no clinical benefit. The molecular underpinnings of ICI resistance involve intricate cell-cell interactions that are yet elusive. To systematically map the interactions between malignant and immune cells in the tumor ecosystem, we applied single-cell RNA sequencing to 31 human melanoma tumors, profiling thousands of malignant, immune, and stromal cells. We identified a transcriptional program in malignanT-cells that is strongly associated with T-cell exclusion and immunotherapy resistance. Using highly multiplexed in situ imaging we first demonstrated that this program characterizes malignanT-cells in “cold” niches. Next, we showed that the program predicts clinical responses to ICI according to multiple independent validation cohorts, including a new cohort that we obtained from 112 melanoma patients treated with anti-PD-1 therapy. We then identified CDK4/6 as master regulators of this resistance program, and found that CDK4/6 inhibitors repress the program and shift melanoma cells into a senescence-associated secretory phenotype. Lastly, we showed that CDK4/6-inhibition leads to a substantial reduction in melanoma tumor outgrowth in a B16 mouse model when given in combination with immunotherapy. Taken together, our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and forms a basis for the development of novel therapeutic strategies that could overcome immunotherapy resistance. Citation Format: Livnat Jerby, Parin Shah, Michael S. Cuoco, Christopher Rodman, Mei-Ju Su, Johannes M. Melms, Rachel Leeson, Abhay Kanodia, Shaolin Mei, Jia-Ren Lin, Shu Wang, Bokang Rabasha, David Liu, Gao Zhang, Claire Margolais, Orr Ashenberg, Patrick A. Ott, Elizabeth I. Buchbinder, Riz Haq, Stephen Hodi, Genevieve M. Boland, Ryan J. Sullivan, Dennie Frederick, Benchun Miao, Tabea Moll, Keith Flaherty, Meenhard Herlyn, Russell S. Jenkins, Rohit Thummalapalli, Monika S. Kowalczyk, Israel Canadas, Bastian Schilling, Adam N.R Cartwright, Adrienne M. Luoma, Shruti Malu, Patrick Hwu, Chantale Bernatchez, Marie-Andree Forget, David A. Barbie, Alex K. Shalek, Itay Tirosh, Peter K. Sorger, Kai W. Wucherpfennig, Eliezer M. Van Allen, Dirk Schadendorf, Bruce E. Johnson, Asaf Rotem, Orit Rosenblatt-Rozen, Levi A. Garraway, Charles H. Yoon, Benjamin Izar, Aviv Regev. Single-cell RNA-sequencing of metastatic melanoma identifies a cancer cell-intrinsic program associated with immune checkpoint inhibitor resistance [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A082.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-A082
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    Abstract 5877: Intratumoral lymphocyte networks harbor TCF1+ PD1+ progenitor CD8 T cells in lung cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5877-5877
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5877-5877
    Abstract: Cancer immunotherapies that activate cytotoxic T cell responses against tumors have been remarkably effective in some patients, but the determinants of response remain unclear. To investigate how spatial organization of T cells might influence immunotherapy response, we developed a tissue-based cyclic immunofluorescence (t-CyCIF) platform to characterize preclinical genetically engineered mouse models (GEMMs) of cancer. We optimized a 21-antibody panel delineating major myeloid and lymphoid cell subsets, that included key markers for characterizing T cell phenotypes and function. The panel was used to characterize the Kras/p53-mutant GEMM of lung adenocarcinoma, treated with anti-PD-1/anti-CTLA-4 immune checkpoint blockade (ICB) therapy or a neoantigen-targeted long-peptide vaccine. Spatial profiling by t-CyCIF identified intratumoral lymphocyte networks (“lymphonets”) as a key feature associated with a productive immune response against lung tumors. Lymphonets were predominantly composed of B cells and conventional CD4 T cells, but harbored tumor-reactive CD8 T cell populations. TCF1+ PD1+ progenitor CD8 T cells, a subset previously correlated with patient response to ICB, were almost exclusively localized to lymphonets inside tumors. Lymphonets of similar composition harboring TCF1+ PD1+ cells were also found in early-stage human lung adenocarcinomas. In response to ICB and vaccine therapies in mice, cytotoxic CD8 T cells (Granzyme B+/Perforin+) colocalized with TCF1+ PD1+ cells in lymphonets, likely having differentiated from this progenitor pool. Notably, vaccination further induced a highly proliferative (Ki67hi) and cytotoxic (GranzymeBhiPerforinhi) population of CD8 T cells localized outside of tumors that we posit enter tumors without passing through the intratumoral progenitor cell state. Upon becoming dysfunctional, marked by loss of Granzyme B/Perforin expression and upregulation of inhibitory receptors, CD8 T cells were excluded from lymphonets and localized predominantly to the tumor margin. Altogether, these results shed light on the spatial dynamics associated with a productive response to immunotherapies and open avenues for exploration into the function of lymphonets in supporting cytotoxic CD8 T cell responses in tumors. Citation Format: Megan L. Burger, Giorgio Gaglia, Claire C. Ritch, Danae Rammos, Yang Dai, Grace E. Crossland, Sara Z. Tavana, Simon Warchol, Alex M. Jaeger, Santiago Naranjo, Shannon Coy, Ajit J. Nirmal, Robert Krueger, Jia-Ren Lin, Hanspeter Pfister, Peter K. Sorger, Tyler Jacks, Sandro Santagata. Intratumoral lymphocyte networks harbor TCF1+ PD1+ progenitor CD8 T cells in lung cancer [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5877.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-5877
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    detail.hit.zdb_id: 410466-3
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