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  • American Association for Cancer Research (AACR)  (18)
  • 1
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    Online Resource
    Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Immunology Research Vol. 10, No. 8 ( 2022-08-03), p. 996-1012
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 10, No. 8 ( 2022-08-03), p. 996-1012
    Abstract: Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-21-0870
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    Abstract 3165: Stroma-immune landscape in lymphoma: new mechanisms of immunosuppression and therapeutic targeting
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 3165-3165
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 3165-3165
    Abstract: Tumor cells engage in bidirectional interactions with stroma and immune cells to promote disease progression and immune evasion. Stroma-specific gene signatures have been associated with outcome in diffuse large B-cell lymphoma (DLBCL), but their immunobiology has been understudied. To characterize the stromal landscape in lymphoma, we performed high-dimensional imaging mass cytometry analysis of the major stroma subsets and revealed a marked expansion and remodeling of the immuno-specialized fibroblastic reticular cells (FRCs) in human DLBCL biopsies (n=53). The FRC network was similarly remodeled in tumors from the IμBcl6 transgenic model of lymphoma, and aberrant fibroblasts were in close proximity to cancer cells. Modelling the interactions between murine and patient FRCs and tumor cells, using 2D and 3D cultures, showed that lymphoma drives the acquisition of an inflammatory-like, pro-tumoral (upregulation of fibroblast activating protein-α, FAP) phenotype and associated functional capabilities. Comparative bulk transcriptomic analysis revealed that lymphoma-FRCs undergo transcriptional reprogramming and activate gene pathways associated with inflammatory responses. Moreover, single-cell RNA-seq revealed an expansion of activated FRC clusters expressing B cell supporting genes, while T cell-associated FRCs were contracted. Altered chemokine signaling pathways in DLBCL-FRCs were functionally linked to reduced attraction of T cells and impeded migration along the lymphoma-reticular network. Moreover, lymphoma-FRCs upregulated expression of inhibitory PD-1 ligands that reduced the anti-tumor cytolytic activity of CD8+ T cells, a T cell bispecific antibody (CD20-TCB, glofitamab) and anti-CD19 CAR T cells in our coculture models. To overcome the immunosuppressive activity of DLBCL-FRCs, we investigated the use of CD20-TCB in combination with stroma-targeting immunocytokine fusion protein drug (FAP-IL2v, RG7461) or costimulatory fusion protein (FAP-4-1BBL, RG7827). Functional cytotoxicity assays using human and murine primary DLBCL patient samples revealed that both stroma-targeting drugs paired effectively with the CD20-TCB to enhance the cytotoxic activity of autologous CD8+ T cells. In addition, the ability of immune-/stroma- targeted combination immunotherapy to trigger anti-tumor activity and CD8+ T cell retention within the FRC-TME was demonstrated using 3D precision-cut lymph node slice-based organotypic cultures of DLBCL and other B cell malignancies. In conclusion our data reveal that lymphoma cells actively reprogram FRCs that acquire altered immunoregulatory function which prevents effective T cell motility and suppresses the anti-tumor function of cytolytic T cells. Importantly, we demonstrate that combination immunotherapy incorporating fibroblast-targeting fusion proteins could effectively recover anti-tumor T cell activity. Citation Format: Benedetta Apollonio, Nedyalko Petrov, Filomena Spada, Peter Jarvis, Domenico Cozzetto, Shichina Kannambath, David Kuo, Mansoor Saqui, Rose-Marie Amini, Gunilla Enblad, Graham Charlotte, Reuben Benjamin, Anna Vardi, Elisabeth Phillips, Jon Salisbury, Eric N. Olson, Brian Fox, Patrick Hagner, Anita Gandhi, Ruth F. Jarrett, Sylvia Herter, Marina Bacac, Christina Klaus, Christian Klein, Alexander Deutsch, Alan G. Ramsay. Stroma-immune landscape in lymphoma: new mechanisms of immunosuppression and therapeutic targeting [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 3165.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-3165
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 3
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    Abstract PO-096: The synaptic protein Netrin G1 ligand (NGL-1) modulates tumorigenesis and immunosuppression in pancreatic cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 22_Supplement ( 2021-11-15), p. PO-096-PO-096
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 22_Supplement ( 2021-11-15), p. PO-096-PO-096
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer, with a 5-year survival of 10%. A major feature of PDAC is the presence of a dense fibrous stroma, due to the expansion of cancer associated fibroblasts (CAFs) and their extracellular matrix. This unique environment represents a challenge for therapies as it promotes immunosuppression, limits access to nutrients, and excludes or inactivates antitumor immune cells. Recently, we identified the ectopic expression of the neuronal protein Netrin G1 Ligand (NGL-1) in PDAC tissue, including its novel expression in immune cells and CAFs. However, the roles of NGL-1 in the tumor microenvironment (TME) of PDAC and in immune cell function are unknown and warranted further investigation. The contribution of NGL-1 to PDAC tumorigenesis was assessed by measuring the expression of NGL-1 in different models of PDAC and by orthotopically injecting PDAC cells in wild type (WT) or NGL-1 full body knockout mice (KO). Using our in vitro 3D system we evaluated if NGL-1+ CAFs, compared to NGL-1 knockdown (KD) CAFs, produced less immunosuppressive factors and were able to rescue PDAC cell survival under nutrient deprivation. For NGL-1 dependent immune cell functions we isolated naïve immune cells from WT and KO mice and performed ex-vivo functional assays. NGL-1 expression in fibroblasts correlated with disease development in different models of PDAC, and myeloid, T and NK cells from tumor bearing mice tended to overexpress NGL-1 when compared with cells from naïve mice. Accordingly, NGL-1 KO mice orthotopically injected with PDAC cells developed smaller tumors with decreased secretion of immunosuppressive factors, increased presence of CD8+ T cells and CD4+ T cells expressing less pro-tumor markers. Single cell RNA sequencing data from tumors from KO mice showed downregulation of pro-tumor genes in different cell populations, with the fibroblastic populations differing between WT and KO mice. In order to evaluate the contribution of the immune system for tumorigenesis in WT and KO mice, we performed bone marrow chimeras and depletion of specific immune cells. Functionally, CD8+ and CD4+ T cells from KO mice proliferated more when stimulated in vitro, suggesting that NGL-1 could represent a functional brake for T cells, inhibiting their anti-tumor capacity. The lack of NGL-1 in stimulated bone marrow-derived macrophages decreased pro-inflammatory cytokine secretion, further suggesting a functional role for NGL-1 in myeloid cells. Of note, NGL-1 KD CAFs did not support PDAC cell survival in vitro and produced less immunosuppressive cytokines, which was phenocopied by the treatment with a peptide targeting NGL-1. Translationally, we assessed the overall survival of 140 PDAC patients according to NGL-1 expression in the TME, where low expression of NGL-1 in CAFs and immune cells correlated with better survival of PDAC patients. Overall, this suggests NGL-1 as potential new target in PDAC, that could be manipulated in different compartments in pancreatic cancer. Citation Format: Debora Barbosa Vendramini Costa, Ralph Francescone, Janusz Franco-Barraza, Tiffany Luong, Nina Steele, Benjamin Allen, Marina Pasca di Magliano, Charline Ogier, Igor Astsaturov, Kathy Q. Cai, Andres J. Klein-Szanto, Huamin Wang, Kerry Campbell, Edna Cukierman. The synaptic protein Netrin G1 ligand (NGL-1) modulates tumorigenesis and immunosuppression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-096.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA21-PO-096
    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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    Bioactivity and Prognostic Significance of Growth Differentiation Factor GDF15 Secreted by Bone Marrow Mesenchymal Stem Cells in Multiple Myeloma
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 6 ( 2012-03-15), p. 1395-1406
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 6 ( 2012-03-15), p. 1395-1406
    Abstract: Overexpression of growth differentiation factor 15 (GDF15) by bone marrow mesenchymal stem cells occurs widely in patients with multiple myeloma, but the pathophysiologic effects of GDF15 in this setting remain undefined. GDF15 has been described in numerous solid tumors but never in hematologic malignancies. In this study, we report that GDF15 significantly increases survival of stroma-dependent multiple myeloma cells including primary multiple myeloma cells. In particular, GDF15 conferred resistance to melphalan, bortezomib, and to a lesser extent, lenalidomide in both stroma-dependent and stroma-independent multiple myeloma cells. Akt-dependent signaling was critical to mediate the effects of GDF15, whereas Src and extracellular signal-regulated kinase 1/2 signaling pathways were not involved. Given these results, we tested the clinical significance of plasma concentrations of GDF15 (pGDF15) in 131 patients with multiple myeloma and found that it correlated with disease prognosis. Specifically, patients with high levels of pGDF15 had lower probabilities of event-free and overall survival 30 months after diagnosis than patients with low pGDF15 levels. Our findings suggest that tumor microenvironment-derived GDF15 is a key survival and chemoprotective factor for multiple myeloma cells, which is pathophysiologically linked to both initial parameters of the disease as well as patient survival. Cancer Res; 72(6); 1395–406. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-11-0188
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 5
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    HOXB13 Mutation and Prostate Cancer: Studies of Siblings and Aggressive Disease
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 22, No. 4 ( 2013-04-01), p. 675-680
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 22, No. 4 ( 2013-04-01), p. 675-680
    Abstract: Background: Recent work detected for the first time a high-risk prostate cancer mutation, in homeobox B13 (HOXB13) among European-Americans. Methods: We further evaluated this G84E missense mutation (rs138213197) in two genetic association studies of prostate cancer: a family-based study of brothers and a case–control study of more aggressive disease (N = 2,665 total). We then calculated overall impact of this mutation by pooling all published studies of European-Americans. Results: In our studies, the mutation was found exclusively among men with prostate cancer (carrier frequency = 1.48%) or unaffected brothers of cases carrying the mutation (frequency = 0.34%), and carrying the mutation gave an OR for disease = 4.79 (P = 0.01). The G84E mutation was more common among men with an earlier age of onset (≤55 years) or a family history of prostate cancer. We also observed for the first time an African-American case carrying the G84E mutation, although at HOXB13 both of his chromosomes were of European-American ancestry. The pooled analysis also indicated that carrying the G84E mutation results in an almost five-fold increase in risk of prostate cancer (P = 3.5 × 10−17), and this risk is even higher among cases with an early age of prostate cancer onset (≤55 years) or a family history of disease: a test of heterogeneity across these strata gives P & lt; 1 × 10−5. Conclusions: The HOXB13 mutation substantially increases risk of early onset, familial prostate cancer in European-American men. Impact: Testing for the G84E mutation in men with a positive family history may help distinguish those who merit more regular screening for prostate cancer. Cancer Epidemiol Biomarkers Prev; 22(4); 675–80. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-12-1154
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 6
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    Abstract 3649: Stromal netrinG1-ligand (NGL1) constitutes a new modulator of pancreatic cancer immunosuppression
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3649-3649
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3649-3649
    Abstract: Pancreatic cancer (PC), is currently the third and predicted to soon become the second deadliest cancer in the US. A unique feature of PC is its fibrous tumor microenvironment (TME), marked by the expansion of cancer-associated fibroblasts (CAFs), highly bundled collagen I, and absence or inactivation of antitumor immune cells. As this TME is a physical and biochemical therapeutic barrier, a better understanding of how pro-tumor immunosuppression is modulated constitutes a highly sought-after goal. Herein we report that in addition to the identified ectopic expression of NetrinG1-Ligand (NGL1) in PC cells, NGL1 is detected in both immune cells and CAFs, with increased levels in CAFs associated with short PC patient overall survival. Further, in tumor-bearing mice, fibroblastic NGL1 expression correlates with PC progression while assorted immune cells express high levels of NGL1. To question the pro-PC role of stromal NGL1, we evaluated tumor progression in NGL1 knockout (KO) mice, using orthotopic PC allografts, and observed that tumors were significantly smaller. Single-cell RNA sequencing pointed to downregulation of pro-tumor transcripts in key assorted KO TME cells (e.g., T Cells). We also noted that tumor-bearing KO tissues included a TME with limited immunosuppressive cytokines, increased CD8+ and CD4+ T cells expressing low levels of tumor-promoting factors, and a limited amount of desmoplastic bundled collagen, all suggestive of a TGFβ-deficient milieu. In order to further dissect between the NGL1-dependent contributions of hematopoietic/immune vs. local stroma (e.g., CAFs) cells, we generated bone marrow KO/WT chimeras. Results suggested that loss of NGL1 in one of the two compartments fails to phenocopy the full-body loss of NGL1, and was thus insufficient to hinder PC tumorigenesis. Further, depletion of selected immune cell subsets informed on NGL1-dependent T- and myeloid-cell contributions. Functional assays showed that KO macrophages released limited pro-tumor factors while KO T cells displayed increased proliferation compared to the WTs of both cell types. Fibroblastic NGL1-dependent immuno-regulatory effects were confirmed with human immune cells collected from healthy donors. Mechanistically, while immune cells and CAFs deficient in NGL1 are both tumor-suppressive, the latter can regain pro-tumor functions in response to TGFβ, explaining the chimera and full-body KO results. Finally, KO effects were mirrored in WT CAFs treated with an NGL1-neutralizing molecule. Overall, our data suggest that stromal NGL1 is a novel and targetable modulator of PC immunosuppression Citation Format: Débora B. Vendramini-Costa, Ralph Francescone, Janusz Franco-Barraza, Tiffany Luong, Esteban Martinez, Stephen Sykes, Nina G. Steele, Benjamin L. Allen, Marina Pasca di Magliano, Dmitry I. Zhigarev, Charline Ogier, Igor Astsaturov, Kathy Q. Cai, Andres J. Klein-Szanto, Huamin Wang, Kerry Campbell, Edna Cukierman. Stromal netrinG1-ligand (NGL1) constitutes a new modulator of pancreatic cancer immunosuppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3649.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-3649
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 7
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    Abstract GS3-10: Partitioning of cancer therapeutics in nuclear condensates
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 4_Supplement ( 2021-02-15), p. GS3-10-GS3-10
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. GS3-10-GS3-10
    Abstract: The molecules of the cell are compartmentalized into membrane- and non-membrane-bound organelles. Many non-membrane-bound organelles are phase-separated biomolecular condensates with distinct physicochemical properties that can absorb and concentrate specific proteins and nucleic acids involved in discrete biochemical processes. We reasoned that selective condensate partitioning might also occur with small molecule drugs whose targets occur within condensates, and that the therapeutic index and efficacy of such compounds might therefore relate to their ability to partition into condensates. To test this idea, we focused our study on nuclear condensates reported in cell lines, demonstrated they occur in normal human and malignant breast cancer, and developed assays to test clinically active antineoplastic small molecule drugs relative to these condensates.To study the behavior of drugs within condensates, these were modeled in vitro with purified proteins and visualized by fluorescent confocal microscopy. We found that cisplatin, tamoxifen, JQ1, THZ1, and mitoxantrone are concentrated in specific protein condensates in vitro, and that this occurs through physicochemical properties independent of the drug target. For each drug, the small molecule partitioned into the same condensate in vitro in which its established target resides in vivo. A screen of a chemically diverse fluorescent probes and mutant-protein condensates demonstrated that pi-system interactions between aromatic moieties in the protein and small molecule govern concentration in condensates. These results show that clinically important drugs partition into specific protein condensates in vitro by virtue of defined chemical properties, thereby altering their local concentration.Alkylating agents are a class of commonly used antineoplastic compounds, of which cisplatin is a prominent example. In vitro droplet assays revealed that cisplatin is selectively concentrated in transcriptional condensates, and that this ability is required for efficient platination of target DNA. In cell studies revealed that cisplatin preferentially targets DNA contained within MED1 condensates, and disrupts the genetic regulatory elements that compose phase-separated transcriptional condensates. Live cell imaging demonstrated that transcriptional condensates are dissolved by cisplatin, whereas other condensates remain intact. Thus, we conclude that cisplatin preferentially modifies transcriptional condensate-associated DNA in cells, and that this causes selective condensate disruption. The mechanisms that produce drug resistance can provide clues to drug activity in the clinical setting. Investigating the behavior of tamoxifen within ER transcriptional condensates demonstrated that it disrupts these condensates in vitro and on oncogenes in cells; hormonal therapy resistant ESR1 mutations render these condensates resistant. MED1 overexpression, a poorly understood mechanism of tamoxifen resistance, increased the size of ER-MED1 condensates, thereby rending tamoxifen more dilute and ineffective when concentrated therein. This suggest that altering the size and nature of transcription condensates in breast cancer can mediate drug resistance in the clinical setting.Our results show that antineoplastic drugs partition selectively into condensates, that this can occur through physicochemical properties independent of their molecular targets, and that resistance to drugs may occur through condensate altering mechanisms. These results have implications for development of efficacious cancer therapeutics; effective target engagement will depend on factors such as drug partitioning in condensates. Assays of the type described here may thus help optimize condensate partitioning, target engagement, and the therapeutic index of drugs for cancer treatment. Citation Format: Isaac Klein, Ann Boija, Lena Afeyan, Susana Wilson Hawken, Mengyang Fan, Alessandra Dall'Agnese, Ozgur Oksuz, Jonathan Henninger, Krishna Shrinivas, Benjamin Sabari, Ido Sagi, Victoria Clark, Jesse Platt, Mrityunjoy Kar, Patrick McCall, Alicia Zamudio, John Mantiega, Eliot Coffey, Charles Li, Nancy Hannett, Yang Guo, Tim-Michael Decker, Tong Lee, Tinghu Zhang, Jing-Ke Weng, Dylan Taatjes, Arup Chakraborty, Phillip Sharp, Young Tae Chang, Anthony Hyman, Nathanael Gray, Richard Young. Partitioning of cancer therapeutics in nuclear condensates [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-10.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS20-GS3-10
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
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    Abstract PR05: A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 6_Supplement_2 ( 2020-06-01), p. PR05-PR05
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 6_Supplement_2 ( 2020-06-01), p. PR05-PR05
    Abstract: Background: Persons of African ancestry (AA) experience a 1.5-2-fold risk of multiple myeloma (MM) compared to persons of European ancestry (EA). We assembled a set of MM patients with self-reported AA in order to evaluate the contribution of genetics to etiology in this high-risk group. Methods: Here we present the results of a meta-analysis of two GWAS in 1,813 cases and 8,871 controls of AA. We also conducted an admixture mapping scan to identify risk alleles associated with local ancestry, fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA, and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. Finally, we conducted an eQTL analysis measuring gene expression in those genes harboring a risk variant in malignant plasma cells from 292 of the patients from a single site. Results: In GWAS analysis, we identified two suggestive novel loci located at 9p24.3 and 9p13.1 at P & lt;1 × 10-6, but no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. 20 of the 23 known EA risk variants showed directional consistency and 9 replicated at P & lt;0.05 in AA individuals. In eight regions, we identified markers that better capture MM risk in persons of AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95%CI: 1.56, 2.11) increased MM risk compared to those with average risk (25-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P= 5.1 × 10–12). Conclusion: Our study shows that common genetic variation contributes to MM risk individuals of AA. This abstract is also being presented as Poster C040. Citation Format: Zhaohui Du, Niels Weinhold, Gregory Chi Song, Kristen A. Rand, David J. Van Den Berg, Amie E. Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William J. Blot, Graham Casey, Victoria L. Stevens, Rick Kittles, Phyllis J. Goodman, W. Ryan Diver, Anselm Hennis, Barbara Nemesure, Eric A. Klein, Benjamin A. Rybicki, Janet L. Stanford, John S. Witte, Lisa Signorello, Esther M. John, Leslie Bernstein, Antoinette Stroup, Owen W. Stephens, Maurizio Zangari, Frits Van Rhee, Andrew Olshan, Wei Zheng, Jennifer J. Hu, Regina Ziegler, Sarah J. Nyante, Sue Ann Ingles, Michael Press, John David Carpten, Stephen Chanock, Jayesh Mehta, Graham A Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Kenneth C. Anderson, Loic Le Marchand, Daniel Auclair, Brian C.-H. Chiu, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen. A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR05.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1538-7755.DISP19-PR05
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 9
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    Abstract 4158: Selective targeting of CD122 combined with radiotherapy triggers CD8 and NK mediated immunity, abrogating metastasis in head and neck squamous cell carcinoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4158-4158
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4158-4158
    Abstract: The implementation of cancer immunotherapies, while revolutionary in certain cancer types, has seen limited clinical success in head and neck squamous cell carcinomas (HNSCC). This revelation has prompted investigation in alternative targets to invigorate anti-tumor immunity. IL-2 signaling governs the survival and functionality of lymphocytes, thus making IL-2 receptor signaling an attractive target for new immunotherapies. However, therapies to enhance IL-2 signaling are often limited in their efficacy by modulating the activation of regulatory T cells (Tregs), which preferentially binds IL-2 via the high affinity receptor IL-2Rα (CD25). Selectively targeting IL2Rβ (CD122), the intermediate affinity receptor, can be leveraged to induce anti-tumor immune responses in effector T cells and natural killer (NK) cells while limiting negative regulation conferred by Tregs. The novel bispecific immunocytokine PD1-IL2v preferentially activates IL-2 signaling through CD122 on PD-1 expressing cells, activating immune effectors, and preventing immune exhaustion by blockade of PD-1. However, PD-1 blockade can amplify immunosuppression by Tregs, necessitating their depletion using αCD25. Here, we observe that radiation therapy and combination of PD1-IL2v with an Fc-optimized αCD25 antibody induces systemic activation of effector CD4 and CD8 T cells, reducing overall tumor burden. Concordant with improved local tumor control, we also observed a decrease in metastatic spread using a newly developed Kras/smad4/p53 mutated metastatic tumor model. NK cells, which are known to play a central role in the control of tumor cell dissemination though direct cytotoxicity, displayed a phenotypic shift towards an activated state upon treatment with PD1-IL2v, highlighted by enhanced cytotoxicity, NK receptor diversity, and metabolic activity. Although relatively uncommon in comparison to other cancer types, those patients who present with metastases display a substantially poorer outcome, demonstrating the need for therapies which target this axis of cancer disease progression. In summary, we find that radiation therapy and PD1-IL2v imparts potent anti-tumor immunity, reducing local tumor growth and distant tumor spread, which taken together contribute to increased overall survival. Citation Format: Jacob Gadwa, Maria Amann, Thomas E. Bickett, Michael W. Knitz, Laurel B. Darragh, Miles Piper, Benjamin Van Court, Sanjana Bukkapatanam, Tiffany T. Pham, Xiao-Jing Wang, Laura Codarri Deak, Christian Klein, Pablo Umana, Angelo D'Alessandro, Sana Karam. Selective targeting of CD122 combined with radiotherapy triggers CD8 and NK mediated immunity, abrogating metastasis in head and neck squamous cell carcinoma. [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 4158.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-4158
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract 5106: The addition of radiation therapy to simultaneous targeting of PD-1 and IL2Rβγ enhances antigen-specific CD8 T cell anti-tumor immunity in pancreatic cancer models
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5106-5106
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5106-5106
    Abstract: Although IL-2 has been shown to critically mediate NK and T cell effector functions, when used in clinical trials this cytokine has failed due to toxicity and severe side effects of the systemic treatment. Our lab has investigated the use of a next-generation IL-2 compound, murine PD1-IL2v, which consists of an anti-PD-1 antibody fused to a IL2-variant with abolished binding to IL2Rα. Previous work shows this molecule results in tumor-antigen specific T cell expansion and differentiation towards immune effectors. Here, we report for the first time that radiation therapy amplifies the anti-tumor effect observed with PD1-IL2v treatment of murine orthotopic models of local tumor growth and metastasis. This anti-tumor effect is correlated with increases in proliferative and polyfunctional CD8 T cells across tumor, lymph node, and blood compartments. Furthermore, using an OVA-antigen specific orthotopic model, we found that radiation in combination with PD1-IL2v treatment enhances infiltration and activation of antigen-specific CD8 T cells, which have been shown to be critical for immunotherapy clinical success. A portion of tumor-bearing mice treated with radiation and PD1-IL2v fully eradicated their primary tumors and tumor rechallenges, which we show correlates with increased markers of memory in CD8 T cells of these mice. To demonstrate the clinical relevance of these preclinical findings, we performed RNA sequencing on paired pancreatic adenocarcinoma (PDAC) patient tumor tissue samples prior to and following radiation. We observed enhanced IL2Rβ and IL2Rγ expression as well as IL2R signaling in PDAC-patient responders to radiation therapy compared to non-responders. In conclusion, the antigen-specific, lasting memory response to preclinical PDAC models demonstrated here provides rationale for the treatment of PDAC with a radiation and PD1-IL2v combination. Citation Format: Maureen Hoen, Miles Piper, Laurel B. Darragh, Diemmy Nugyen, Jacob Gadwa, Maria Amann, Greta Durini, Michael Knitz, Benjamin Van Court, Tiffany Pham, Ross Kedl, Pablo Umana, Laura Codarri-Deak, Christian Klein, Angelo D’Alessandro, Sana D. Karam. The addition of radiation therapy to simultaneous targeting of PD-1 and IL2Rβγ enhances antigen-specific CD8 T cell anti-tumor immunity in pancreatic cancer models. [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 5106.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-5106
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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