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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/075465 Al 4 May 20 17 (04.05.2017) W P O P C T (51) International Patent Classification: (72) Inventors; and A61K 39/00 (2006.01) C12N 5/0783 (2010.01) (71) Applicants : REGEV, Aviv [IL/US]; 15A Ellsworth Ave, A61K 35/17 (2015.01) G01N 33/50 (2006.01) Cambridge, MA 02139 (US). ANDERSON, Ana Carri- zosa [US/US]; 110 Cypress Street, Unit 3 11, Brookline, (21) International Application Number: MA 02445 (US). CONG, Le [CN/US]; 100 Memorial PCT/US20 16/059487 Drive, Apt. 8-21B, Cambridge, MA 02142 (US). KU- (22) International Filing Date: CHROO, Vijay, K. [IN/US]; 30 Fairhaven Road, Newton, 28 October 2016 (28.10.201 6) MA 02149 (US). SINGER, Meromit [US/US]; 10 Bel mont Place, Somerville, MA 02143 (US). WANG, Chao English (25) Filing Language: [US/US]; 6 Canal Park, Unit 302, Cambridge, MA 02 141 (26) Publication Language: English (US). (30) Priority Data: (74) Agents: SCHER, Michael, B. et al; Vedder Price P.C., 62/247,446 28 October 2015 (28. 10.2015) US 1633 Broadway, New York, NY 10019 (US). 62/384,577 7 September 2016 (07.09.2016) US (81) Designated States (unless otherwise indicated, for every (71) Applicants: THE BROAD INSTITUTE INC. [US/US]; kind of national protection available): AE, AG, AL, AM, 415 Main Street, Cambridge, MA 02142 (US). MAS¬ AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, SACHUSETTS INSTITUTE OF TECHNOLOGY BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, [US/US]; 77 Massachusetts Ave., Cambridge, MA 02142 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (US). THE BRIGHAM AND WOMEN'S HOSPITAL, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, INC. [US/US]; 75 Francis Street, Boston, MA 021 15 (US). KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, [Continued on nextpage] (54) Title: COMPOSITIONS AND METHODS FOR EVALUATING AND MODULATING IMMUNE RESPONSES BY DE TECTING AND TARGETING GATA3 (57) Abstract: The present invention provides markers, marker signatures and molecular targets that correlate with dysfunction of immune cells and are ad FIG. 1A vantageously independent of the immune cell activation status. The present markers, marker signatures and molecular targets provide for new ways to evaluate and modulate immune responses. Specifically, GATA3 and/or FOX- Ol modulation are provided for use as markers, marker signatures and molecu lar targets. Therapeutic methods are also provided to treat a patient in need thereof who would benefit from an increased immune response. Tu or dissociation w o 2017/075465 A i III II I I 11 III 11 1II III Hill I I111 lllll lllll 111 llll 11llll OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, ZM, ZW. SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, Published: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, — with international search report (Art. 21(3)) TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, COMPOSITIONS AND METHODS FOR EVALUATING AND MODULATING IMMUNE RESPONSES BY DETECTING AND TARGETING GATA3 RELATED APPLICATIONS AND INCORPORATION BY REFERENCE [0001] This application claims priority and benefit of U.S. provisional application Serial numbers 62/247,446 filed October 28, 20 5 and 62/384,577 filed September 7, 2016 [0002] Reference is made to PCT Publication No. WO/2014/134351 published on February 27, 2014, PCT Publication No. WO/20 14/1 45631 published on September 18, 2014, PCT Publication No. WO/2014/172606 published on October 23, 2014 and PCT Publication No. WO/2015/130968 published on February 26, 2015. Reference is also made to International application serial number PCT/US20 16/0400 15 filed on June 29, 2016. [0003] The foregoing applications, and all documents cited therein or during their prosecution ("appln cited documents") and all documents cited or referenced in the appln cited documents, and all documents cited or referenced herein ("herein cited documents"), and all documents cited or referenced i herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. FEDERAL- FUNDING LEGEND [0004] This invention was made with government support under MH105960, NS045937, AI073748 and CA1 87975 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION [0005] The invention relates to substances, compositions and methods useful in evaluating and modulating immune responses. BACKGROUND OF THE INVENTION [0006] T ceil fitness is closely linked to health and disease. Activated CD8~ T lymphocytes have been reported to exist in various functional states characterized by different cytokine secretion potentials, proliferation capabilities and the ability and potential to become long-term memory cells. The types of CD8+ subpopulations and their functional states can vary kineticaliy in response to different pathogens and are dependent on the status of pathogen clearance. Characterizing the different CDS T cell subpopulations and their underlying driving mechanisms is an active field of research contributing to our understanding of protective immunity in successful pathogen clearance, and of T cell regulation during uncontrolled tumor growth and chronic infections. Recent advances on this front have enabled the development of improved vaccines and novel immune-based therapies for various cancers. It is believed that the breadth of the functional potential of CDS T cells is far from understood, and that gaining a deeper understanding will lead to further advancements. [0007] During persistent immune activation, such as uncontrolled tumor growth or chronic viral infections, the ability of CD8 lvmphocvtes to secrete pro-inflammatory cytokines and elaborate cytotoxic function becomes compromised to different extents (Anderson et al., 2016, Immunity 44, 989-1004; Baitsch et al., 2012, Trends Immunol 33, 364-372; Kim and Ahmed, 2010, Curr Opin Immunol 22, 223-230; Wherry and Kurachi, 2015, Nature reviews Immunology 15, 486-499; Zuniga et al., 2015, Annu Rev Virol 2, 573-597). These CD8+ populations are frequently referred to as "dysfunctional" or "exhausted", and are believed to constitute a barrier to successful anti-tumor and anti-viral immunity. Such dysfunctional or exhausted CD8+ lymphocytes are typically compromised for their ex vivo cytokine secretion capabilities and are present in an environment in which there is persistent antigen. Gaining a clear molecular understanding of the dysfunctional T cell state can thus help develop successful therapeutic interventions. [0008] Dysfunctional CD8+ T cells can be both protective and detrimental against disease control. Attempts to manipulate pathways associated with T cell dysfunction have resulted in different biological consequences to the host. On one hand, blocking co-inhibitory pathways such as PD-1 and Tim3 that frequently coincide with T cell dysfunction has promoted T cell function and is particularly effective in promoting tumor regression in several types of cancer. On the other hand, the targeted deletion of PD-1 at disease onset causes immune pathology and death of the host in a chronic viral infection model, suggesting that T cell dysfunction may have evolved to prevent immunopathology (Barber et al., 2006, Nature, vol. 439, 682-687). Also, current therapies targeting co-inhibitory or immune checkpoint receptors such as CTLA-4 and PD-1 that are highly expressed on dysfunctional T cells are showing promise in the clinic. However, not all patients respond and some cancers remain largely refractory to these therapies. Furthermore, depletion of exhausted T ceils by targeting known regulators such as Tbet and Eomes resulted in high viral load suggesting that dysfunctional T cells provide partially effective immune control (Paley et ai., 2012, Science, vol. 338, 1220-1225). These findings highlight the complex roles of dysfunctional CDS T cells during unsuccessful antigen clearance. The ability to delineate the diverse roles of dysfunctional CDS' T cells at the molecular level can help with more specific targeting of truly exhausted T cells while sparing those dysfunctional T cells that may be still protective. [0009] C T cell function is associated with their cytokine profiles. It has been reported that effector CDS T cells with the ability to simultaneously produce multiple cytokines (polyfunctional CDS ' T cells) are associated with protective immunity in patients with controlled chrome viral infections as well as cancer patients responsive to immune therapy (Spranger et al., 2014, J . Immunother. Cancer, vol. 2, 3). In the presence of persistent antigen CDS ' T cells were found to have lost cytolytic activity completely over time (Moskophidis et al., 1 93, Nature, vol. 362, 758-761). It was subsequently found that dysfunctional T cells can differentially produce IL-2, TNFa and FNg in a hierarchical order (Wherry et al., 2003, J .
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    Overexpressed WDR3 Induces the Activation of Hippo Pathway by Interacting with GATA4 in Pancreatic Cancer Wenjie Su Sichuan Provincial People's Hospital: Sichuan Academy of Medical Sciences and Sichuan People's Hospital Shikai Zhu Sichuan Provincial People's Hospital: Sichuan Academy of Medical Sciences and Sichuan People's Hospital Kai Chen Sichuan Provincial People's Hospital: Sichuan Academy of Medical Sciences and Sichuan People's Hospital Hongji Yang Sichuan Provincial People's Hospital: Sichuan Academy of Medical Sciences and Sichuan People's Hospital Mingwu Tian Sichuan Provincial People's Hospital: Sichuan Academy of Medical Sciences and Sichuan People's Hospital Qiang Fu Massachusetts General Hospital Ganggang Shi University of British Columbia School of Human Kinetics: The University of British Columbia School of Kinesiology Shijian Feng University of British Columbia School of Human Kinetics: The University of British Columbia School of Kinesiology Dianyun Ren Wuhan Union Hospital Xin Jin Wuhan Union Hospital Chong Yang ( [email protected] ) Sichuan Provincial People's Hospital: Sichuan Academy of Medical Sciences and Sichuan People's Hospital Page 1/34 Research Keywords: Pancreatic Cancer, WDR3, GATA4, YAP1, Hippo Signaling Pathway Posted Date: November 13th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-104564/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published on March 1st, 2021. See the published version at https://doi.org/10.1186/s13046-021-01879-w. Page 2/34 Abstract Background: WD repeat domain 3 (WDR3) is involved in a variety of cellular processes including gene regulation, cell cycle progression, signal transduction and apoptosis.
  • Table S1. Quantitative RT-PCR Primer and Sirna Sequences Gene Name

    Table S1. Quantitative RT-PCR Primer and Sirna Sequences Gene Name

    Table S1. Quantitative RT-PCR Primer and siRNA Sequences Gene Name Gene RefSeq or GenBank Forward Primer Reverse Primer siRNA Name siRNA Sequence (plus) siRNA Sequence Symbol Accession (minus/guide) a disintegrin and metalloproteinase domain 9 ADAM9 NM_003816 ACCTCAGCAGTTCCCATCAA TAAAGGAGGTGCAGGAGCAG siADAM9_1 GAGATTAACTAGAGAAAGA TCTTTCTCTAGTTAATCTC (meltrin gamma) siADAM9_2 GGAGGGAGTTCATAATTCA TGAATTATGAACTCCCTCC guanine nucleotide binding protein (G protein), GNAI3 NM_006496 TCTGTTATAGTTGGCGGCAGT ATTCTGCAAAGGCAAAAGGA siGNAI3_1 AGAACTAGCAGGAGTGATT AATCACTCCTGCTAGTTCT alpha inhibiting activity polypeptide 3 siGNAI3_2 ACACAGGTTCCAATACATA TATGTATTGGAACCTGTGT AA099748 AA099748 AA099748 CTACCACTGAGGTGTCCCTGT CAGCCATCTAACAGCATTTTT siAA099748_1 GTTAGATGGCTGATTAATA TATTAATCAGCCATCTAAC siAA099748_2 CGACAGAGGAGCAGCATTA TAATGCTGCTCCTCTGTCG calpain 12 CAPN12 NM_144691 GTCCTTCTGTCCCTCATCCA CAGCAGCTCCTCTGGAATCT siCAPN12_1 GGACACGCGTATTCCATCA TGATGGAATACGCGTGTCC siCAPN12_2 AATCCTCAGTTCCGTTTAA TTAAACGGAACTGAGGATT NMDA receptor regulated 1 NARG1 NM_057175 TAAAGGGAATTTGCCGAAGA AGCACTGGAGTTCGGTTTGT siNARG1_1 TGCGAGATCTTGAGGGTTA TAACCCTCAAGATCTCGCA siNARG1_2 GATAGGAGGTCCAAAAGAA TTCTTTTGGACCTCCTATC AK091308 AK091308 AK091308 TCTCCTGAATGGGAGGAATG GGCAACAGATGTTTCCTGTG siAK091308_1 CCAAAGACTTAGACTGTAA TTACAGTCTAAGTCTTTGG siAK091308_2 GCACAAAGCATTTACAACA TGTTGTAAATGCTTTGTGC serine/threonine kinase 24 (STE20 homolog, STK24 NM_003576 GCATCTGCCTTCCTTATCCA TGACAGTGTTTTGCCAGAGG siSTK24_1 TCGATTATCTCCATTCGGA TCCGAATGGAGATAATCGA yeast) siSTK24_2 CATCGGACTTGGACAGAAA