Combined Analysis of Antigen Presentation and T-cell Recognition Reveals Restricted Immune Responses in Melanoma.

Abstract:

:The quest for tumor-associated antigens (TAA) and neoantigens is a major focus of cancer immunotherapy. Here, we combine a neoantigen prediction pipeline and human leukocyte antigen (HLA) peptidomics to identify TAAs and neoantigens in 16 tumors derived from seven patients with melanoma and characterize their interactions with their tumor-infiltrating lymphocytes (TIL). Our investigation of the antigenic and T-cell landscapes encompassing the TAA and neoantigen signatures, their immune reactivity, and their corresponding T-cell identities provides the first comprehensive analysis of cancer cell T-cell cosignatures, allowing us to discover remarkable antigenic and TIL similarities between metastases from the same patient. Furthermore, we reveal that two neoantigen-specific clonotypes killed 90% of autologous melanoma cells, both in vitro and in vivo, showing that a limited set of neoantigen-specific T cells may play a central role in melanoma tumor rejection. Our findings indicate that combining HLA peptidomics with neoantigen predictions allows robust identification of targetable neoantigens, which could successfully guide personalized cancer immunotherapies.Significance: As neoantigen targeting is becoming more established as a powerful therapeutic approach, investigating these molecules has taken center stage. Here, we show that a limited set of neoantigen-specific T cells mediates tumor rejection, suggesting that identifying just a few antigens and their corresponding T-cell clones could guide personalized immunotherapy. Cancer Discov; 8(11); 1366-75. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1333.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

Kalaora S,Wolf Y,Feferman T,Barnea E,Greenstein E,Reshef D,Tirosh I,Reuben A,Patkar S,Levy R,Quinkhardt J,Omokoko T,Qutob N,Golani O,Zhang J,Mao X,Song X,Bernatchez C,Haymaker C,Forget MA,Creasy C,Greenberg P,

doi

10.1158/2159-8290.CD-17-1418

subject

Has Abstract

pub_date

2018-11-01 00:00:00

pages

1366-1375

issue

11

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-17-1418

journal_volume

8

pub_type

杂志文章
  • Sending CAR T Cells After Multiple Myeloma.

    abstract::Preliminary results from an ongoing phase I clinical trial in China suggest that chimeric antigen receptor T cells engineered to home in on a protein called BCMA may be a potent therapeutic option for multiple myeloma. The therapy was well tolerated and induced complete, durable responses in patients with relapsed/ref...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-088

    authors:

    更新日期:2017-08-01 00:00:00

  • Insights into Epigenetic Remodeling in VHL-Deficient Clear Cell Renal Cell Carcinoma.

    abstract:: Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the von Hippel-Lindau tumor suppressor gene (VHL), and the functional tumorigenic consequences of this loss have been used to develop therapies for advanced ccRCC, such as targeting activation of the HIF pathway. Yao and colleagues elucidate how ...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-17-0971

    authors: Ricketts CJ,Linehan WM

    更新日期:2017-11-01 00:00:00

  • LXR agonism inhibits metastatic melanoma through activation of ApoE.

    abstract::Nuclear hormone receptor targeting suppresses melanoma progression in diverse preclinical models. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2014-056

    authors:

    更新日期:2014-05-01 00:00:00

  • Unfurling the Genetic Map of Sarcomas.

    abstract::An international team of researchers has uncovered multiple new germline mutations that may influence the development of sarcomas. Notably, they found that variants in several DNA damage sensing and repair genes contribute greatly to sarcoma risk, including BRCA2, ATM, ATR, and ERCC2. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2016-108

    authors:

    更新日期:2016-10-01 00:00:00

  • New FDA Center May Speed Approval Process.

    abstract::The FDA's new Oncology Center of Excellence is aimed at consolidating the approval processes for new cancer drugs, biologics, and devices. Richard Pazdur, MD, current director of the agency's Office of Hematology and Oncology Products within the Center for Drug Evaluation and Research will serve as the new center's ac...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2016-092

    authors:

    更新日期:2016-09-01 00:00:00

  • An ADC for Triple-Negative Breast Cancer.

    abstract::A phase II study indicates that sacituzumab govitecan (IMMU-132), a Trop-2-specific antibody linked to the irinotecan metabolite SN-38, prolongs the progression-free survival of patients with advanced triple-negative breast cancer. IMMU-132 is well tolerated, causing fewer and more manageable side effects than irinote...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2015-162

    authors:

    更新日期:2016-01-01 00:00:00

  • Regulatory T-cell Response to Enterotoxigenic Bacteroides fragilis Colonization Triggers IL17-Dependent Colon Carcinogenesis.

    abstract:UNLABELLED:Many epithelial cancers are associated with chronic inflammation. However, the features of inflammation that are procarcinogenic are not fully understood. Regulatory T cells (Treg) typically restrain overt inflammatory responses and maintain intestinal immune homeostasis. Their immune-suppressive activity ca...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-15-0447

    authors: Geis AL,Fan H,Wu X,Wu S,Huso DL,Wolfe JL,Sears CL,Pardoll DM,Housseau F

    更新日期:2015-10-01 00:00:00

  • Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis.

    abstract::Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/β-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a hi...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-19-0532

    authors: Kato S,Weng QY,Insco ML,Chen KY,Muralidhar S,Pozniak J,Diaz JMS,Drier Y,Nguyen N,Lo JA,van Rooijen E,Kemeny LV,Zhan Y,Feng Y,Silkworth W,Powell CT,Liau BB,Xiong Y,Jin J,Newton-Bishop J,Zon LI,Bernstein BE,Fish

    更新日期:2020-07-01 00:00:00

  • PI3K Inhibitor Improves PFS in BELLE-2 Trial.

    abstract::Adding a PI3K inhibitor to anti-estrogen receptor therapy may be a viable treatment option for women with advanced hormone receptor-positive breast cancer that becomes resistant to endocrine therapy, according to findings from the phase III BELLE-2 trial, presented at the 2015 San Antonio Breast Cancer Symposium. ...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2015-176

    authors:

    更新日期:2016-02-01 00:00:00

  • Gilead Buys into Tizona's Anti-HLA-G Strategy.

    abstract::Gilead announced plans in July to pay $300 million for a 49.9% stake in Tizona Therapeutics, with the option to buy the rest of the company for $1.25 billion. Whether Gilead follows through with the acquisition will hinge on how well Tizona's investigational HLA-G inhibitor, TTX-080, fares in early-stage clinical tria...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2020-077

    authors:

    更新日期:2020-10-01 00:00:00

  • ARID1A mutations in cancer: another epigenetic tumor suppressor?

    abstract:UNLABELLED:Although disordered chromatin organization has long been recognized as a feature of cancer, the molecular underpinnings of chromatin structure, epigenetic regulation, and their relationships to transcription are only beginning to be understood. Cancer genome sequencing studies have revealed a novel theme: fr...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-12-0361

    authors: Wu JN,Roberts CW

    更新日期:2013-01-01 00:00:00

  • Pazopanib outscores sunitinib on tolerability.

    abstract::In a phase III trial for patients with metastatic renal cell carcinoma, pazopanib and sunitinib offered comparable progression-free survival, but pazopanib scored higher on quality-of-life indices. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2013-131

    authors:

    更新日期:2014-01-01 00:00:00

  • T-DM1 Combo Graduates from I-SPY 2.

    abstract::The combination of the antibody-drug conjugate ado-trastuzumab emtansine, or T-DM1, plus pertuzumab given prior to surgery outperformed standard therapy in women with HER2-positive breast cancer enrolled in the I-SPY 2 trial. The results, reported at the American Association for Cancer Research Annual Meeting 2016, su...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2016-048

    authors:

    更新日期:2016-06-01 00:00:00

  • Recurrent Fusions in MYB and MYBL1 Define a Common, Transcription Factor-Driven Oncogenic Pathway in Salivary Gland Adenoid Cystic Carcinoma.

    abstract:UNLABELLED:Adenoid cystic carcinoma (ACC), the second most common malignancy of salivary glands, is a rare tumor with a bleak prognosis for which therapeutic targets are unavailable. We used RNA sequencing (RNA-seq) to analyze low-quality RNA from archival, formaldehyde-fixed, paraffin-embedded samples. In addition to ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-15-0859

    authors: Brayer KJ,Frerich CA,Kang H,Ness SA

    更新日期:2016-02-01 00:00:00

  • Olaparib shows promise in multiple tumor types.

    abstract::A phase II study of the PARP inhibitor olaparib (AstraZeneca) for cancer patients with inherited BRCA1 and BRCA2 gene mutations confirmed earlier results showing clinical benefit for advanced breast and ovarian cancers, and demonstrated evidence of effectiveness against pancreatic and prostate cancers. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2013-082

    authors:

    更新日期:2013-07-01 00:00:00

  • New Method Enables Development of Customized Vasculature in Organoids.

    abstract::Transduction of ETV2 restored blood vessel-forming capabilities to mature human endothelial cells. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2020-135

    authors:

    更新日期:2020-11-01 00:00:00

  • BRAF Dimerization: An Underlying Resistance Mechanism in Low-Grade Pediatric Gliomas.

    abstract:: BRAF fusions and mutations are the most frequent genetic alterations in pediatric low-grade gliomas. The work from Wang and colleagues identifies an acquired secondary BRAF mutation that confers resistance to pharmacologic BRAF inhibition in a BRAFV600E glioma. The authors demonstrate that the mu...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-18-0784

    authors: Romano G,Kwong LN

    更新日期:2018-09-01 00:00:00

  • Suppression of Metastases Using a New Lymphocyte Checkpoint Target for Cancer Immunotherapy.

    abstract:UNLABELLED:CD96 has recently been shown as a negative regulator of mouse natural killer (NK)-cell activity, with Cd96(-/-)mice displaying hyperresponsive NK cells upon immune challenge. In this study, we have demonstrated that blocking CD96 with a monoclonal antibody inhibited experimental metastases in three different...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-15-0944

    authors: Blake SJ,Stannard K,Liu J,Allen S,Yong MC,Mittal D,Aguilera AR,Miles JJ,Lutzky VP,de Andrade LF,Martinet L,Colonna M,Takeda K,Kühnel F,Gurlevik E,Bernhardt G,Teng MW,Smyth MJ

    更新日期:2016-04-01 00:00:00

  • IDO is a nodal pathogenic driver of lung cancer and metastasis development.

    abstract:UNLABELLED:Indoleamine 2,3-dioxygenase (IDO) enzyme inhibitors have entered clinical trials for cancer treatment based on preclinical studies, indicating that they can defeat immune escape and broadly enhance other therapeutic modalities. However, clear genetic evidence of the impact of IDO on tumorigenesis in physiolo...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-12-0014

    authors: Smith C,Chang MY,Parker KH,Beury DW,DuHadaway JB,Flick HE,Boulden J,Sutanto-Ward E,Soler AP,Laury-Kleintop LD,Mandik-Nayak L,Metz R,Ostrand-Rosenberg S,Prendergast GC,Muller AJ

    更新日期:2012-08-01 00:00:00

  • Nanostars amplify ability to image cancer.

    abstract::A new nanoparticle design may make cancer detection possible without the use of molecular markers of tumor cells. The star-shaped probe detected five different cancers in mouse models, according to a new study. By using nanostars to boost surface-enhanced resonance Raman scattering signals, the technique highlighted t...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2015-022

    authors:

    更新日期:2015-04-01 00:00:00

  • Blood Monocyte Frequency May Be a Biomarker for Response to Anti-PD-1.

    abstract::CD14+CD16-HLA-DRhi monocyte frequency was linked to response to anti-PD-1 in patients with melanoma. ...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-RW2018-016

    authors:

    更新日期:2018-03-01 00:00:00

  • Epigenetic Identity in AML Depends on Disruption of Nonpromoter Regulatory Elements and Is Affected by Antagonistic Effects of Mutations in Epigenetic Modifiers.

    abstract::We performed cytosine methylation sequencing on genetically diverse patients with acute myeloid leukemia (AML) and found leukemic DNA methylation patterning is primarily driven by nonpromoter regulatory elements and CpG shores. Enhancers displayed stronger differential methylation than promoters, consisting predominan...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-16-1032

    authors: Glass JL,Hassane D,Wouters BJ,Kunimoto H,Avellino R,Garrett-Bakelman FE,Guryanova OA,Bowman R,Redlich S,Intlekofer AM,Meydan C,Qin T,Fall M,Alonso A,Guzman ML,Valk PJM,Thompson CB,Levine R,Elemento O,Delwel R,Meln

    更新日期:2017-08-01 00:00:00

  • ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors.

    abstract:UNLABELLED:ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-14-0849

    authors: Shen J,Peng Y,Wei L,Zhang W,Yang L,Lan L,Kapoor P,Ju Z,Mo Q,Shih IeM,Uray IP,Wu X,Brown PH,Shen X,Mills GB,Peng G

    更新日期:2015-07-01 00:00:00

  • A combined epigenetic therapy equals the efficacy of conventional chemotherapy in refractory advanced non-small cell lung cancer.

    abstract::A new study by Juergens and colleagues provides the first successful example of a combined epigenetic therapy capable of achieving results similar to those of conventional chemotherapy in refractory metastatic non-small cell lung cancer. Furthermore, the authors describe interesting blood-based DNA methylation biomark...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-11-0271

    authors: Rodríguez-Paredes M,Esteller M

    更新日期:2011-12-01 00:00:00

  • How does multistep tumorigenesis really proceed?

    abstract::Identifying the cancer cells-of-origin is of great interest, as it holds the potential to elucidate biologic mechanisms inherent in the normal cell state that have been co-opted to drive the oncogenic cell state. An emerging concept, proposed here, states that cancer stem cells, key players in cancer initiation and me...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-14-0788

    authors: Chaffer CL,Weinberg RA

    更新日期:2015-01-01 00:00:00

  • A Set of Transcriptomic Changes Is Associated with Anti-PD-1 Resistance.

    abstract::The IPRES signature is related to anti-PD-1 response, and high mutational load predicts survival. ...

    journal_title:Cancer discovery

    pub_type: 信件

    doi:10.1158/2159-8290.CD-RW2016-057

    authors:

    更新日期:2016-05-01 00:00:00

  • RAS Mutations Are Not Created Equal.

    abstract::In this issue of Cancer Discovery, Poulin and colleagues apply structural, biochemical, and biological profiling of two mutants of KRAS, one found most frequently in all cancers (G12D) and one found nearly exclusively in colorectal cancer (A146T). They provide compelling evidence that specific mutations will impart di...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-19-0406

    authors: Hobbs GA,Der CJ

    更新日期:2019-06-01 00:00:00

  • Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent.

    abstract:UNLABELLED:Genetic approaches have shown that the p110β isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110β-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collectio...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-12-0003

    authors: Ni J,Liu Q,Xie S,Carlson C,Von T,Vogel K,Riddle S,Benes C,Eck M,Roberts T,Gray N,Zhao J

    更新日期:2012-05-01 00:00:00

  • Innate αβ T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming.

    abstract::Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβ+CD4-CD8-NK1.1- innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ∼10% of T lymphocytes infiltrating PDA in mice and human...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-19-0161

    authors: Hundeyin M,Kurz E,Mishra A,Rossi JAK,Liudahl SM,Leis KR,Mehrotra H,Kim M,Torres LE,Ogunsakin A,Link J,Sears RC,Sivagnanam S,Goecks J,Islam KMS,Dolgalev I,Savadkar S,Wang W,Aykut B,Leinwand J,Diskin B,Adam S,Is

    更新日期:2019-09-01 00:00:00

  • Metabolic Codependencies in the Tumor Microenvironment.

    abstract::Metabolic reprogramming enables cancer cell growth, proliferation, and survival. This reprogramming is driven by the combined actions of oncogenic alterations in cancer cells and host cell factors acting on cancer cells in the tumor microenvironment. Cancer cell intrinsic mechanisms activate signal transduction compon...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-20-1211

    authors: Dey P,Kimmelman AC,DePinho RA

    更新日期:2021-01-27 00:00:00