Publications by authors named "Jesse M Zaretsky"

19 Publications

  • Page 1 of 1

Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma.

Sci Transl Med 2020 10;12(565)

Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, CA 90095, USA.

Defects in tumor-intrinsic interferon (IFN) signaling result in failure of immune checkpoint blockade (ICB) against cancer, but these tumors may still maintain sensitivity to T cell-based adoptive cell therapy (ACT). We generated models of IFN signaling defects in B16 murine melanoma observed in patients with acquired resistance to ICB. Tumors lacking or did not respond to ICB, whereas ACT was effective against tumors, but not tumors, where both type I and II tumor IFN signaling were defective. This was a direct result of low baseline class I major histocompatibility complex (MHC I) expression in B16 and the dependency of MHC I expression on either type I or type II IFN signaling. We used genetic and pharmacologic approaches to uncouple this dependency and restore MHC I expression. Through independent mechanisms, overexpression of NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) and intratumoral delivery of BO-112, a potent nanoplexed version of polyinosinic:polycytidylic acid (poly I:C), each restored the efficacy of ACT against B16- tumors. BO-112 activated double-stranded RNA (dsRNA) sensing (via protein kinase R and Toll-like receptor 3) and induced MHC I expression via nuclear factor κB, independent of both IFN signaling and NLRC5. In summary, we demonstrated that in the absence of tumor IFN signaling, MHC I expression is essential and sufficient for the efficacy of ACT. For tumors lacking MHC I expression due to deficient IFN signaling, activation of dsRNA sensors by BO-112 affords an alternative approach to restore the efficacy of ACT.
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http://dx.doi.org/10.1126/scitranslmed.abb0152DOI Listing
October 2020

Key Parameters of Tumor Epitope Immunogenicity Revealed Through a Consortium Approach Improve Neoantigen Prediction.

Cell 2020 Oct 9;183(3):818-834.e13. Epub 2020 Oct 9.

Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. Electronic address:

Many approaches to identify therapeutically relevant neoantigens couple tumor sequencing with bioinformatic algorithms and inferred rules of tumor epitope immunogenicity. However, there are no reference data to compare these approaches, and the parameters governing tumor epitope immunogenicity remain unclear. Here, we assembled a global consortium wherein each participant predicted immunogenic epitopes from shared tumor sequencing data. 608 epitopes were subsequently assessed for T cell binding in patient-matched samples. By integrating peptide features associated with presentation and recognition, we developed a model of tumor epitope immunogenicity that filtered out 98% of non-immunogenic peptides with a precision above 0.70. Pipelines prioritizing model features had superior performance, and pipeline alterations leveraging them improved prediction performance. These findings were validated in an independent cohort of 310 epitopes prioritized from tumor sequencing data and assessed for T cell binding. This data resource enables identification of parameters underlying effective anti-tumor immunity and is available to the research community.
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http://dx.doi.org/10.1016/j.cell.2020.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652061PMC
October 2020

Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade.

Cancer Discov 2020 Aug 28;10(8):1140-1157. Epub 2020 May 28.

Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, Los Angeles, California.

Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of , and loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with knockout became insensitive to IFN-induced antitumor effects, while knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti-PD-1 therapy . -knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti-PD-1, mediated by natural killer (NK) and CD8 T cells. -knockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy. SIGNIFICANCE: The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416458PMC
August 2020

Expression-Based Cell Lineage Analysis in Through a Course-Based Research Experience for Early Undergraduates.

Authors:
John M Olson Cory J Evans Kathy T Ngo Hee Jong Kim Joseph Duy Nguyen Kayla G H Gurley Truc Ta Vijay Patel Lisa Han Khoa T Truong-N Letty Liang Maggie K Chu Hiu Lam Hannah G Ahn Abhik Kumar Banerjee In Young Choi Ross G Kelley Naseem Moridzadeh Awais M Khan Omair Khan Szuyao Lee Elizabeth B Johnson Annie Tigranyan Jay Wang Anand D Gandhi Manish M Padhiar Joseph Hargan Calvopina Kirandeep Sumra Kristy Ou Jessie C Wu Joseph N Dickan Sabrena M Ahmadi Donald N Allen Van Thanh Mai Saif Ansari George Yeh Earl Yoon Kimberly Gon John Y Yu Johnny He Jesse M Zaretsky Noemi E Lee Edward Kuoy Alexander N Patananan Daniel Sitz PhuongThao Tran Minh-Tu Do Samira J Akhave Silverio D Alvarez Bobby Asem Neda Asem Nicole A Azarian Arezou Babaesfahani Ahmad Bahrami Manjeet Bhamra Ragini Bhargava Rakesh Bhatia Subir Bhatia Nicholas Bumacod Jonathan J Caine Thomas A Caldwell Nicole A Calica Elise M Calonico Carman Chan Helen H-L Chan Albert Chang Chiaen Chang Daniel Chang Jennifer S Chang Nauman Charania Jasmine Y Chen Kevin Chen Lu Chen Yuyu Chen Derek J Cheung Jesse J Cheung Jessica J Chew Nicole B Chew Cheng-An Tony Chien Alana M Chin Chee Jia Chin Youngho Cho Man Ting Chou Ke-Huan K Chow Carolyn Chu Derrick M Chu Virginia Chu Katherine Chuang Arunit Singh Chugh Mark R Cubberly Michael Guillermo Daniel Sangita Datta Raj Dhaliwal Jenny Dinh Dhaval Dixit Emmylou Dowling Melinda Feng Christopher M From Daisuke Furukawa Himaja Gaddipati Lilit Gevorgyan Zunera Ghaznavi Tulika Ghosh Jaskaran Gill David J Groves Kalkidan K Gurara Ali R Haghighi Alexandra L Havard Nasser Heyrani Tanya Hioe Kirim Hong Justin J Houman Molly Howland Elaine L Hsia Justin Hsueh Stacy Hu Andrew J Huang Jasmine C Huynh Jenny Huynh Chris Iwuchukwu Michael J Jang An An Jiang Simran Kahlon Pei-Yun Kao Manpreet Kaur Matthew G Keehn Elizabeth J Kim Hannah Kim Michelle J Kim Shawn J Kim Aleksandar Kitich Ross A Kornberg Nicholas G Kouzelos Jane Kuon Bryan Lau Roger K Lau Rona Law Huy D Le Rachael Le Carrou Lee Christina Lee Grace E Lee Kenny Lee Michelle J Lee Regina V Lee Sean H K Lee Sung Kyu Lee Sung-Ling D Lee Yong Jun Lee Megan J Leong David M Li Hao Li Xingfu Liang Eric Lin Michelle M Lin Peter Lin Tiffany Lin Stacey Lu Serena S Luong Jessica S Ma Li Ma Justin N Maghen Sravya Mallam Shivtaj Mann Jason H Melehani Ryan C Miller Nitish Mittal Carmel M Moazez Susie Moon Rameen Moridzadeh Kaley Ngo Hanh H Nguyen Kambria Nguyen Thien H Nguyen Angela W Nieh Isabella Niu Seo-Kyung Oh Jessica R Ong Randi K Oyama Joseph Park Yaelim A Park Kimberly A Passmore Ami Patel Amy A Patel Dhruv Patel Tirth Patel Katherine E Peterson An Huynh Pham Steven V Pham Melissa E Phuphanich Neil D Poria Alexandra Pourzia Victoria Ragland Riki D Ranat Cameron M Rice David Roh Solomon Rojhani Lili Sadri Agafe Saguros Zainab Saifee Manjot Sandhu Brooke Scruggs Lisa M Scully Vanessa Shih Brian A Shin Tamir Sholklapper Harnek Singh Sumedha Singh Sondra L Snyder Katelyn F Sobotka Sae Ho Song Siddharth Sukumar Halley C Sullivan Mark Sy Hande Tan Sara K Taylor Shivani K Thaker Tulsi Thakore Gregory E Tong Jacinda N Tran Jonathan Tran Tuan D Tran Vivi Tran Cindy L Trang Hung G Trinh Peter Trinh Han-Ching H Tseng Ted T Uotani Akram V Uraizee Kent K T Vu Kevin K T Vu Komal Wadhwani Paluk K Walia Rebecca S Wang Shuo Wang Stephanie J Wang Danica D Wiredja Andrew L Wong Daniel Wu Xi Xue Griselda Yanez Yung-Hsuan Yang Zhong Ye Victor W Yee Cynthia Yeh Yue Zhao Xin Zheng Anke Ziegenbalg Jon Alkali Ida Azizkhanian Akash Bhakta Luke Berry Ryen Castillo Sonja Darwish Holly Dickinson Ritika Dutta Rahul Kumar Ghosh Riley Guerin Jonathan Hofman Garrick Iwamoto Sarah Kang Andrew Kim Brian Kim Hanwool Kim Kristine Kim Suji Kim Julie Ko Michael Koenig Alejandro LaRiviere Clifton Lee Jiwon Lee Brandon Lung Max Mittelman Mark Murata Yujin Park Daniel Rothberg Ben Sprung-Keyser Kunal Thaker Vivian Yip Paul Picard Francie Diep Nikki Villarasa Volker Hartenstein Casey Shapiro Marc Levis-Fitzgerald Leslie Jaworski David Loppato Ira E Clark Utpal Banerjee

G3 (Bethesda) 2019 11 5;9(11):3791-3800. Epub 2019 Nov 5.

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095

A variety of genetic techniques have been devised to determine cell lineage relationships during tissue development. Some of these systems monitor cell lineages spatially and/or temporally without regard to gene expression by the cells, whereas others correlate gene expression with the lineage under study. The AL4 echnique for eal-time nd lonal xpression (G-TRACE) system allows for rapid, fluorescent protein-based visualization of both current and past GAL4 expression patterns and is therefore amenable to genome-wide expression-based lineage screens. Here we describe the results from such a screen, performed by undergraduate students of the University of California, Los Angeles (UCLA) Undergraduate Research Consortium for Functional Genomics (URCFG) and high school summer scholars as part of a discovery-based education program. The results of the screen, which reveal novel expression-based lineage patterns within the brain, the imaginal disc epithelia, and the hematopoietic lymph gland, have been compiled into the G-TRACE Expression Database (GED), an online resource for use by the research community. The impact of this discovery-based research experience on student learning gains was assessed independently and shown to be greater than that of similar programs conducted elsewhere. Furthermore, students participating in the URCFG showed considerably higher STEM retention rates than UCLA STEM students that did not participate in the URCFG, as well as STEM students nationwide.
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http://dx.doi.org/10.1534/g3.119.400541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829132PMC
November 2019

Sensitive Detection and Analysis of Neoantigen-Specific T Cell Populations from Tumors and Blood.

Cell Rep 2019 09;28(10):2728-2738.e7

Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Blvd., Pasadena, CA 91125, USA; Institute for Systems Biology, Seattle, WA 98109, USA. Electronic address:

Neoantigen-specific T cells are increasingly viewed as important immunotherapy effectors, but physically isolating these rare cell populations is challenging. Here, we describe a sensitive method for the enumeration and isolation of neoantigen-specific CD8+ T cells from small samples of patient tumor or blood. The method relies on magnetic nanoparticles that present neoantigen-loaded major histocompatibility complex (MHC) tetramers at high avidity by barcoded DNA linkers. The magnetic particles provide a convenient handle to isolate the desired cell populations, and the barcoded DNA enables multiplexed analysis. The method exhibits superior recovery of antigen-specific T cell populations relative to literature approaches. We applied the method to profile neoantigen-specific T cell populations in the tumor and blood of patients with metastatic melanoma over the course of anti-PD1 checkpoint inhibitor therapy. We show that the method has value for monitoring clinical responses to cancer immunotherapy and might help guide the development of personalized mutational neoantigen-specific T cell therapies and cancer vaccines.
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http://dx.doi.org/10.1016/j.celrep.2019.07.106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774618PMC
September 2019

Tumor Characteristics Associated with Benefit from Pembrolizumab in Advanced Non-Small Cell Lung Cancer.

Clin Cancer Res 2019 08 21;25(16):5061-5068. Epub 2019 May 21.

David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California.

Purpose: Several biomarkers have been individually associated with response to PD-1 blockade, including PD-L1 and tumor mutational burden (TMB) in non-small cell lung cancer (NSCLC), and CD8 cells in melanoma. We sought to examine the relationship between these distinct variables with response to PD-1 blockade and long-term benefit.

Experimental Design: We assessed the association between baseline tumor characteristics (TMB, PD-L1, CD4, and CD8) and clinical features and outcome in 38 patients with advanced NSCLC treated with pembrolizumab (median follow-up of 4.5 years, range 3.8-5.5 years).

Results: PD-L1 expression and CD8 infiltration correlated with each other and each significantly associated with objective response rate (ORR) and progression-free survival (PFS). TMB was independent of PD-L1 and CD8 expression, and trended towards association with ORR and PFS. There was no association between CD4 infiltration and outcomes. Only PD-L1 expression was correlated with overall survival (OS). Among 5 patients with long-term survival >3 years with no additional systemic therapy, PD-L1 expression was the only discriminating feature. The increased predictive value for PFS and OS of composite biomarker inclusive of PD-L1, CD8, CD4, and TMB was limited.

Conclusions: In patients with NSCLC treated with PD-1 blockade with long-term follow up, TMB, PD-L1, and CD8 were each associated with benefit from PD-1 blockade. Pretreatment PD-L1 expression was correlated with T lymphocyte infiltration and OS, whereas models incorporating TMB and infiltrating CD4 and CD8 lymphocytes did not substantially add to the predictive value of PD-L1 alone for OS.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901027PMC
August 2019

T cell antigen discovery via trogocytosis.

Nat Methods 2019 02 28;16(2):183-190. Epub 2019 Jan 28.

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

T cell receptor (TCR) ligand discovery is essential for understanding and manipulating immune responses to tumors. We developed a cell-based selection platform for TCR ligand discovery that exploits a membrane transfer phenomenon called trogocytosis. We discovered that T cell membrane proteins are transferred specifically to target cells that present cognate peptide-major histocompatibility complex (MHC) molecules. Co-incubation of T cells expressing an orphan TCR with target cells collectively presenting a library of peptide-MHCs led to specific labeling of cognate target cells, enabling isolation of these target cells and sequencing of the cognate TCR ligand. We validated this method for two clinically employed TCRs and further used the platform to identify the cognate neoepitope for a subject-derived neoantigen-specific TCR. Thus, target cell trogocytosis is a robust tool for TCR ligand discovery that will be useful for studying basic tumor immunology and identifying new targets for immunotherapy.
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http://dx.doi.org/10.1038/s41592-018-0305-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719556PMC
February 2019

T cell antigen discovery via signaling and antigen-presenting bifunctional receptors.

Nat Methods 2019 02 28;16(2):191-198. Epub 2019 Jan 28.

Department of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.

CD8 T cells recognize and eliminate tumors in an antigen-specific manner. Despite progress in characterizing the antitumor T cell repertoire and function, the identification of target antigens remains a challenge. Here we describe the use of chimeric receptors called signaling and antigen-presenting bifunctional receptors (SABRs) in a cell-based platform for T cell receptor (TCR) antigen discovery. SABRs present an extracellular complex comprising a peptide and major histocompatibility complex (MHC), and induce intracellular signaling via a TCR-like signal after binding with a cognate TCR. We devised a strategy for antigen discovery using SABR libraries to screen thousands of antigenic epitopes. We validated this platform by identifying the targets recognized by public TCRs of known specificities. Moreover, we extended this approach for personalized neoantigen discovery.
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http://dx.doi.org/10.1038/s41592-018-0304-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755906PMC
February 2019

Genetic Mechanisms of Immune Evasion in Colorectal Cancer.

Cancer Discov 2018 06 6;8(6):730-749. Epub 2018 Mar 6.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of and genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion. This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-1327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984687PMC
June 2018

High response rate to PD-1 blockade in desmoplastic melanomas.

Nature 2018 01 10;553(7688):347-350. Epub 2018 Jan 10.

University of California Los Angeles, Los Angeles, California, USA.

Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57-81%), including nineteen patients (32%) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF1 mutations (fourteen out of seventeen cases) in these tumours. Immunohistochemistry analysis from nineteen desmoplastic melanomas and thirteen non-desmoplastic melanomas revealed a higher percentage of PD-L1-positive cells in the tumour parenchyma in desmoplastic melanomas (P = 0.04); these cells were highly associated with increased CD8 density and PD-L1 expression in the tumour invasive margin. Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.
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http://dx.doi.org/10.1038/nature25187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773412PMC
January 2018

Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression.

Cell Rep 2017 05;19(6):1189-1201

Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, CA 90095, USA. Electronic address:

PD-L1 and PD-L2 are ligands for the PD-1 immune inhibiting checkpoint that can be induced in tumors by interferon exposure, leading to immune evasion. This process is important for immunotherapy based on PD-1 blockade. We examined the specific molecules involved in interferon-induced signaling that regulates PD-L1 and PD-L2 expression in melanoma cells. These studies revealed that the interferon-gamma-JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis primarily regulates PD-L1 expression, with IRF1 binding to its promoter. PD-L2 responded equally to interferon beta and gamma and is regulated through both IRF1 and STAT3, which bind to the PD-L2 promoter. Analysis of biopsy specimens from patients with melanoma confirmed interferon signature enrichment and upregulation of gene targets for STAT1/STAT2/STAT3 and IRF1 in anti-PD-1-responding tumors. Therefore, these studies map the signaling pathway of interferon-gamma-inducible PD-1 ligand expression.
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http://dx.doi.org/10.1016/j.celrep.2017.04.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420824PMC
May 2017

Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations.

Cancer Discov 2017 02 30;7(2):188-201. Epub 2016 Nov 30.

University of California, Los Angeles (UCLA), Los Angeles, California.

Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2-inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair-deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK1/2 mutations, which led to a lack of PD-L1 expression upon interferon gamma exposure mediated by an inability to signal through the interferon gamma receptor pathway. JAK1/2 loss-of-function alterations in The Cancer Genome Atlas confer adverse outcomes in patients. We propose that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.

Significance: A key functional result from somatic JAK1/2 mutations in a cancer cell is the inability to respond to interferon gamma by expressing PD-L1 and many other interferon-stimulated genes. These mutations result in a genetic mechanism for the absence of reactive PD-L1 expression, and patients harboring such tumors would be unlikely to respond to PD-1 blockade therapy. Cancer Discov; 7(2); 188-201. ©2016 AACR.See related commentary by Marabelle et al., p. 128This article is highlighted in the In This Issue feature, p. 115.
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http://dx.doi.org/10.1158/2159-8290.CD-16-1223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296316PMC
February 2017

Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells.

Cancer Immunol Res 2016 10 2;4(10):845-857. Epub 2016 Sep 2.

Division of Hematology/Oncology, Department of Medicine, University of California (UCLA), Los Angeles, California. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California. Jonsson Comprehensive Cancer Center (JCCC) at UCLA, Los Angeles, California. Division of Surgical Oncology, Department of Surgery, UCLA, Los Angeles, California.

The programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues, and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor-host interactions, we evaluated three syngeneic murine tumor models, the BRAF-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAF mutation and PTEN loss (BRAF/PTEN). Anti-PD-1 or anti-PD-L1 therapy engendered strong antitumor activity against MC38 and YUMM2.1, but not YUMM1.1. PD-L1 expression did not differ between the three models at baseline or upon interferon stimulation. Whereas mutational load was high in MC38, it was lower in both YUMM models. In YUMM2.1, the antitumor activity of PD-1 blockade had a critical requirement for both CD4 and CD8 T cells, as well as CD28 and CD80/86 costimulation, with an increase in CD11cCD11bMHC-II dendritic cells and tumor-associated macrophages in the tumors after PD-1 blockade. Compared with YUMM1.1, YUMM2.1 exhibited a more inflammatory profile by RNA sequencing analysis, with an increase in expression of chemokine-trafficking genes that are related to immune cell recruitment and T-cell priming. In conclusion, response to PD-1 blockade therapy in tumor models requires CD4 and CD8 T cells and costimulation that is mediated by dendritic cells and macrophages. Cancer Immunol Res; 4(10); 845-57. ©2016 AACR.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050168PMC
http://dx.doi.org/10.1158/2326-6066.CIR-16-0060DOI Listing
October 2016

Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.

N Engl J Med 2016 Sep 13;375(9):819-29. Epub 2016 Jul 13.

From the University of California, Los Angeles (UCLA) (J.M.Z., A.G.-D., D.S.S., H.E.-O., W.H., S.H.-L., D.Y.T., G.A.-R., S.S., L.B., J.S., B.H.M., B.C., K.R., I.P.S., P.J.S., C.P.-S., G.C., E.S., X.K., J.P., B.B.-M., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.), and Jonsson Comprehensive Cancer Center (B.C., B.C.-A., T.G.G., P.C.T., R.S.L., A.R.) - both in Los Angeles; and the Division of Immunology, Netherlands Cancer Institute, Amsterdam (R.M., T.N.M.S.).

Background: Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.

Methods: We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later.

Results: Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.

Conclusions: In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1604958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007206PMC
September 2016

Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.

Cell 2016 Mar 17;165(1):35-44. Epub 2016 Mar 17.

Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1662, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA. Electronic address:

PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.
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http://dx.doi.org/10.1016/j.cell.2016.02.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808437PMC
March 2016

Genetic basis for clinical response to CTLA-4 blockade in melanoma.

N Engl J Med 2014 Dec 19;371(23):2189-2199. Epub 2014 Nov 19.

Department of Medicine (A.S., T.M., M.A.P., J.D.W.), Human Oncology and Pathogenesis Program (A.S., V.M., A.D., L.A.W., K.K., T.A.C.), Swim across America-Ludwig Collaborative Research Laboratory (T.M., Y.L., C.E., C.L., J.D.W.), Department of Radiation Oncology (T.A.C.), Department of Pathology (T.J.H.), and Immunology Program, Ludwig Center for Cancer Immunotherapy (J.Y., P.W., T.S.H., J.D.W.), Memorial Sloan Kettering Cancer Center; Weill Cornell Medical College (A.S., M.A.P., J.D.W., T.A.C.); and Department of Mathematics, Columbia University (C.B.) - all in New York; the Department of Molecular and Medical Pharmacology (J.M.Z., A.R.) and the Department of Medicine, Division of Hematology-Oncology, Jonsson Comprehensive Cancer Center (A.R.), University of California, Los Angeles, Los Angeles; and Bristol-Myers Squibb, Princeton, NJ (C.T.H., L.W.).

Background: Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells.

Methods: We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients.

Results: Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab.

Conclusions: These findings define a genetic basis for benefit from CTLA-4 blockade in melanoma and provide a rationale for examining exomes of patients for whom anti-CTLA-4 agents are being considered. (Funded by the Frederick Adler Fund and others.).
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http://dx.doi.org/10.1056/NEJMoa1406498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315319PMC
December 2014

Genomewide clonal analysis of lethal mutations in the Drosophila melanogaster eye: comparison of the X chromosome and autosomes.

Authors:
Gerald B Call John M Olson Jiong Chen Nikki Villarasa Kathy T Ngo Allison M Yabroff Shawn Cokus Matteo Pellegrini Elena Bibikova Chris Bui Albert Cespedes Cheryl Chan Stacy Chan Amrita K Cheema Akanksha Chhabra Vida Chitsazzadeh Minh-Tu Do Q Angela Fang Andrew Folick Gelsey L Goodstein Cheng R Huang Tony Hung Eunha Kim William Kim Yulee Kim Emil Kohan Edward Kuoy Robert Kwak Eric Lee JiEun Lee Henry Lin H-C Angela Liu Tatiana Moroz Tharani Prasad Sacha L Prashad Alexander N Patananan Alma Rangel Desiree Rosselli Sohrab Sidhu Daniel Sitz Chelsea E Taber Jingwen Tan Kasey Topp PhuongThao Tran Quynh-Minh Tran Mary Unkovic Maggie Wells Jessica Wickland Kevin Yackle Amir Yavari Jesse M Zaretsky Christopher M Allen Latifat Alli Ju An Abbas Anwar Sonia Arevalo Danny Ayoub Shawn S Badal Armonde Baghdanian Arthur H Baghdanian Sara A Baumann Vivian N Becerra Hei J Chan Aileen E Chang Xibin A Cheng Mabel Chin Fleurette Chong Carlyn Crisostomo Sanjit Datta Angela Delosreyes Francie Diep Preethika Ekanayake Mark Engeln Elizabeth Evers Farzin Farshidi Katrina Fischer Arlene J Formanes Jun Gong Riju Gupta Blake E Haas Vicky Hahm Michael Hsieh James Z Hui Mei L Iao Sophia D Jin Angela Y Kim Lydia S-H Kim Megan King Chloe Knudsen-Robbins David Kohanchi Bogdana Kovshilovskaya Amy Ku Raymond W Kung Mark E L Landig Stephanie S Latterman Stephanie S Lauw Daniel S Lee Joann S Lee Kai C Lei Lesley L Leung Renata Lerner Jian-ya Lin Kathleen Lin Bryon C Lim Crystal P Y Lui Tiffany Q Liu Vincent Luong Jacob Makshanoff An-Chi Mei Miguel Meza Yara A Mikhaeil Majid Moarefi Long H Nguyen Shekhar S Pai Manish Pandya Aadit R Patel Paul D Picard Michael M Safaee Carol Salame Christian Sanchez Nina Sanchez Christina C Seifert Abhishek Shah Oganes H Shilgevorkyan Inderroop Singh Vanessa Soma Junia J Song Neetika Srivastava Jennifer L StaAna Christie Sun Diane Tan Alison S Teruya Robyn Tikia Trinh Tran Emily G Travis Jennifer D Trinh Diane Vo Thomas Walsh Regan S Wong Katherine Wu Ya-Whey Wu Nkau X V Yang Michael Yeranosian James S Yu Jennifer J Zhou Ran X Zhu Anna Abrams Amanda Abramson Latiffe Amado Jenny Anderson Keenan Bashour Elsa Beyer Allen Bookatz Sarah Brewer Natalie Buu Stephanie Calvillo Joseph Cao Amy Chan Jenny Chan Aileen Chang Daniel Chang Yuli Chang YiBing Chen Joo Choi Jeyling Chou Peter Dang Sumit Datta Ardy Davarifar Artemis Deravanesian Poonam Desai Jordan Fabrikant Shahbaz Farnad Katherine Fu Eddie Garcia Nick Garrone Srpouhi Gasparyan Phyllis Gayda Sherrylene Go Chad Goffstein Courtney Gonzalez Mariam Guirguis Ryan Hassid Brenda Hermogeno Julie Hong Aria Hong Lindsay Hovestreydt Charles Hu Devon Huff Farid Jamshidian James Jen Katrin Kahen Linda Kao Melissa Kelley Thomas Kho Yein Kim Sarah Kim Brian Kirkpatrick Adam Langenbacher Santino Laxamana Janet Lee Chris Lee So-Youn Lee ToHang S Lee Toni Lee Gemma Lewis Sheila Lezcano Peter Lin Thanh Luu Julie Luu Will Marrs Erin Marsh Jamie Marshall Sarah Min Tanya Minasian Helena Minye Amit Misra Miles Morimoto Yasaman Moshfegh Jessica Murray Kha Nguyen Cynthia Nguyen Ernesto Nodado Amanda O'Donahue Ndidi Onugha Nneka Orjiakor Bhavin Padhiar Eric Paul Mara Pavel-Dinu Alex Pavlenko Edwin Paz Sarah Phaklides Lephong Pham Preethi Poulose Russell Powell Aya Pusic Divi Ramola Kirsten Regalia Meghann Ribbens Bassel Rifai Manyak Saakyan Pamela Saarikoski Miriam Segura Farnaz Shadpour Aram Shemmassian Ramnik Singh Vivek Singh Emily Skinner Daniel Solomin Kosha Soneji Kristin Spivey Erika Stageberg Marina Stavchanskiy Leena Tekchandani Leo Thai Jayantha Thiyanaratnam Maurine Tong Aneet Toor Steve Tovar Kelly Trangsrud Wah-Yung Tsang Marc Uemura Emily Vollmer Emily Weiss Damien Wood Joy Wu Sophia Wu Winston Wu Qing Xu Yuki Yamauchi Will Yarosh Laura Yee George Yen Utpal Banerjee

Genetics 2007 Oct 24;177(2):689-97. Epub 2007 Aug 24.

Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California 90095, USA.

Using a large consortium of undergraduate students in an organized program at the University of California, Los Angeles (UCLA), we have undertaken a functional genomic screen in the Drosophila eye. In addition to the educational value of discovery-based learning, this article presents the first comprehensive genomewide analysis of essential genes involved in eye development. The data reveal the surprising result that the X chromosome has almost twice the frequency of essential genes involved in eye development as that found on the autosomes.
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http://dx.doi.org/10.1534/genetics.107.077735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2034635PMC
October 2007