DOCSLIB.ORG

Somatic Mutations and Neoepitope Homology in Melanomas Treated

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Somatic Mutations and Neoepitope Homology in Melanomas Treated Published OnlineFirst December 12, 2016; DOI: 10.1158/2326-6066.CIR-16-0019 Research Article Cancer Immunology Research Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade Tavi Nathanson1, Arun Ahuja1, Alexander Rubinsteyn1, Bulent Arman Aksoy1, Matthew D. Hellmann2,3, Diana Miao4,5, Eliezer Van Allen4,5, Taha Merghoub2,3,6, Jedd D. Wolchok2,3,6, Alexandra Snyder2,3, and Jeff Hammerbacher1 Abstract Immune checkpoint inhibitors are promising treatments for narrowed from somatic mutation burden, to inclusion of only patients with a variety of malignancies. Toward understanding the those mutations predicted to be MHC class I neoantigens, to determinants of response to immune checkpoint inhibitors, it was only including those neoantigens that were expressed or that previously demonstrated that the presence of somatic mutations had homology to pathogens. The only association between is associated with benefit from checkpoint inhibition. A hypoth- somatic mutation burden and response was found when exam- esis was posited that neoantigen homology to pathogens may in ining samples obtained prior to treatment. Neoantigen and part explain the link between somatic mutations and response. To expressed neoantigen burden were also associated with further examine this hypothesis, we reanalyzed cancer exome data response, but neither was more predictive than somatic muta- obtained from our previously published study of 64 melanoma tion burden. Neither the previously described tetrapeptide patients treated with CTLA-4 blockade and a new dataset of RNA- signature nor an updated method to evaluate neoepitope Seq data from 24 of these patients. We found that the ability to homology to pathogens was more predictive than mutation accurately predict patient benefit did not increase as the analysis burden. Cancer Immunol Res; 5(1); 84–91. Ó2016 AACR. Introduction In our study of melanomas treated with checkpoint blockade agents targeting cytotoxic T-lymphocyte associated protein 4 Checkpoint blockade therapies are improving outcomes for (CTLA-4; ref. 8), we present the hypothesis that responding patients with metastatic solid tumors (1–4). As only a subset of tumors may share features with each other or with infectious patients responds, there is a critical need to identify determi- agents and that such resemblance may predict response. In this nants of response. Expression ofprogrammeddeathligandone report, we reanalyzed the data in that study using updated (PD-L1) is the lead companion diagnostic for PD-1/PD-L1 methods and integrating new RNA sequencing (RNA-Seq) data blockade therapies, but sensitivity and specificity are limited from a subset of 24 samples. (5–7). An association between elevated tumor mutation bur- We found that in this small dataset, nonsynonymous mutation den and benefit from checkpoint blockade therapies has been burden was associated with clinical benefit from therapy in demonstrated (8–11). samples collected before, but not after, treatment with CTLA-4 blockade. Predicted neoantigen burden and percentage of C!T 1Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New transitions characteristic of ultraviolet damage were associated York, New York. 2Department of Medicine, Memorial Sloan Kettering Cancer with, but did not outperform, mutation burden. We develop- Center, New York, New York. 3Department of Medicine, Weill Cornell Medical ed a publicly available tool, Topeology (https://github.com/ College, New York, New York. 4Department of Medical Oncology, Dana-Farber hammerlab/topeology), to compare neoantigens to known Cancer Institute, Broad Institute of MIT and Harvard, Boston, Massachusetts. pathogens. Neither the resemblance of tumor neoantigens to 5Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, known antigens nor the previously published tetrapeptide signa- Massachusetts. 6Swim Across America–Ludwig Collaborative Research Labo- ratory, Immunology Program, Ludwig Center for Cancer Immunotherapy, New ture outperformed mutation burden as a predictor of response. York, New York. Note: Supplementary data for this article are available at Cancer Immunology Materials and Methods Research Online (http://cancerimmunolres.aacrjournals.org/). Patient samples T. Nathanson, A. Ahuja, A. Snyder, and J. Hammerbacher contributed equally to All analyzed samples were collected in accordance with local this article. Internal Review Board policies as described in ref. 8 and summa- Online supplementary data files can be found at http://www.hammerlab.org/ rized in Table 1. Thirty-four patients had tumor samples collected melanoma-reanalysis. Epitope comparison tool can be found at https://github. prior to initiating CTLA-4 blockade, and 30 patients had samples com/hammerlab/topeology collected after initiating CTLA-4 blockade. Clinical benefit Corresponding Author: Alexandra Snyder, Memorial Sloan Kettering Cancer was defined as progression-free survival lasting for greater than Center, 300 East 66th Street, New York, NY 10065. Phone: 646-888-5122; Fax: 24 weeks after initiation of therapy (Online Data File 1). Nine 646-888-4265; E-mail: [email protected] discordant lesions were present, where overall patient benefit did doi: 10.1158/2326-6066.CIR-16-0019 not match individual tumor progression. See Table 1 for details Ó2016 American Association for Cancer Research. about this patient cohort. 84 Cancer Immunol Res; 5(1) January 2017 Downloaded from cancerimmunolres.aacrjournals.org on September 24, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst December 12, 2016; DOI: 10.1158/2326-6066.CIR-16-0019 Mutations and Neoepitopes in Melanoma Table 1. Cohort summary 18, 2015, from the MSigDB website (http://www.broadinstitute. Group Benefit No benefit Discordant org/gsea/msigdb/index.jsp). The Hallmark gene set collection was N 27 28 9 extended by adding gene symbols corresponding to well-known % Cutaneous 20/27 19/28 5/9 peptides that are (i) tumor specific; (ii) associated with differen- OS 3.7 (1.6–7.3) 0.8 (0.2–2.7) 4 (1.7–7.9) Age 65 (33–81) 58.5 (18–79) 68 (40–90) tiation; and (iii) overexpressed in cancer cells. To do this, gene Mutations 611 (165–3,394) 321 (6–1,816) 549 (93–1,336) symbols were imported from the Cancer Immunity Peptide Neoantigens 1,388 (209–6,502) 714.5 (3–4,510) 1,048 (197–2,584) Database as gene sets that are compatible with the GSEA software. NOTE: Features of tumors from patients with clinical benefit, no benefit, or in Before running the GSEA, the gene expression data (FPKM) were which a discordant lesion was resected. collapsed using official gene symbol identifiers and the median Abbreviation: OS, overall survival. expression value used when multiple transcripts mapped to the same gene symbol. To normalize the data further, noninformative genes with no variation (SD of 0) across all samples were Mutation calls removed. Three GSEA analyses were conducted comparing: (i) Single-nucleotide variants (SNV) were called with an ensemble pretreatment benefiting versus pretreatment nonbenefiting; (ii) of four variant callers: Mutect, Strelka, SomaticSniper, and Varscan pretreatment benefiting versus posttreatment benefiting; and (iii) as described previously (9). Insertions and deletions (indels) were pretreatment nonbenefiting versus posttreatment nonbenefiting. called using Strelka with default settings In all these comparisons, the normalized gene expression values were used as the input matrix. The number of permutations was HLA typing set to 1,000, restricting these permutations to gene set labels rather HLA types were determined by ATHLATES for all samples using than the sample phenotype labels due to our sample size, and we fi exome sequence data and con rmed with seq2HLA for samples kept the rest of the default options (see http://www.hammerlab. that had RNA-Seq available (24 samples; Online Data File 2). org/melanoma-reanalysis/gsea-results/ for complete reports and instructions to replicate them). Neoepitope prediction Somatic SNVs that occurred a single base away from other Neoantigen homology somatic SNVs were combined into larger variants containing both We developed a tool, Topeology, to compare tumor neoepitopes SNVs. For each somatic variant, we used Topiary (https://github. with entries in the Immune Epitope Database (IEDB; Online Data com/hammerlab/topiary) to generate the predicted 8–11mer File 7; ref. 13), accounting for position, amino acid gaps, and amino acid product resulting from somatic alterations (SNV or biochemical similarity between amino acids. Epitopes were com- indel), including predicted neoepitopes generated from com- pared, and the comparison scored, using the Smith–Waterman bined SNVs (Online Data Files 3–4). Each variant was linked to alignment algorithm (14) supplied with a substitution matrix its corresponding coding DNA sequence (CDS) from Ensembl consisting of PMBEC correlation values derived from the PMBEC based on its B37 coordinates. The CDS sequence was retranslated covariance matrix (15). We compared amino acids from position 3 with the mutated DNA residue producing the mutated peptide to the penultimate amino acid of the peptide, assuming that the product. NetMHCcons v1.1 generated a predicted binding affi- anchor residues would be necessary for MHC class I presentation nity for all 8-mers to 11-mers containing the mutated amino and would therefore not be "visible" to a T cell. A gap penalty equal acid and all peptides with an IC50 score below 500 nmol/L were to the lowest PMBEC correlation
Load more

Recommended publications
  • Tumor Neoantigens: from Basic Research to Clinical Applications
    Jiang et al. Journal of Hematology & Oncology (2019) 12:93 https://doi.org/10.1186/s13045-019-0787-5 REVIEW Open Access Tumor neoantigens: from basic research to clinical applications Tao Jiang1,4†, Tao Shi2†, Henghui Zhang3†,JieHu1, Yuanlin Song1, Jia Wei2*, Shengxiang Ren4* and Caicun Zhou4* Abstract Tumor neoantigen is the truly foreign protein and entirely absent from normal human organs/tissues. It could be specifically recognized by neoantigen-specific T cell receptors (TCRs) in the context of major histocompatibility complexes (MHCs) molecules. Emerging evidence has suggested that neoantigens play a critical role in tumor- specific T cell-mediated antitumor immune response and successful cancer immunotherapies. From a theoretical perspective, neoantigen is an ideal immunotherapy target because they are distinguished from germline and could be recognized as non-self by the host immune system. Neoantigen-based therapeutic personalized vaccines and adoptive T cell transfer have shown promising preliminary results. Furthermore, recent studies suggested the significant role of neoantigen in immune escape, immunoediting, and sensitivity to immune checkpoint inhibitors. In this review, we systematically summarize the recent advances of understanding and identification of tumor- specific neoantigens and its role on current cancer immunotherapies. We also discuss the ongoing development of strategies based on neoantigens and its future clinical applications. Keywords: Neoantigen, Immunotherapy, Immune escape, Immune checkpoint, Resistance Introduction polyomavirus (MCPyV)–related Merkel cell carcinoma Tumor neoantigen, or tumor-specific antigen (TSA), (MCC) and Epstein-Barr virus (EBV)–relatedheadandneck is the repertoire of peptides that displays on the cancers, any epitopes derive from open reading frames tumor cell surface and could be specifically recog- (ORFs) in the viral genome also contribute to the potential nized by neoantigen-specific T cell receptors (TCRs) source of neoantigens [6–8].
    [Show full text]
  • Efficient Tumor Clearance and Diversified Immunity Through Neoepitope Vaccines and Combinatorial Immunotherapy
    Published OnlineFirst July 10, 2019; DOI: 10.1158/2326-6066.CIR-18-0620 Research Article Cancer Immunology Research Efficient Tumor Clearance and Diversified Immunity through Neoepitope Vaccines and Combinatorial Immunotherapy Karin L. Lee1, Stephen C. Benz2, Kristin C. Hicks1, Andrew Nguyen2,Sofia R. Gameiro1, Claudia Palena1, John Z. Sanborn2, Zhen Su3, Peter Ordentlich4, Lars Rohlin5, John H. Lee6, Shahrooz Rabizadeh2,5, Patrick Soon-Shiong2,5, Kayvan Niazi5, Jeffrey Schlom1, and Duane H. Hamilton1 Abstract Progressive tumor growth is associated with deficits in the tumor immunosuppression, and a tumor-targeted IL12 immunity generated against tumor antigens. Vaccines target- molecule to facilitate T-cell function within the tumor ing tumor neoepitopes have the potential to address qualita- microenvironment. Analysis of tumor-infiltrating leuko- tive defects; however, additional mechanisms of immune cytes demonstrated this multifaceted treatment regimen was þ failure may underlie tumor progression. In such cases, patients required to promote the influx of CD8 Tcellsandenhance would benefit from additional immune-oncology agents tar- the expression of transcripts relating to T-cell activation/ geting potential mechanisms of immune failure. This effector function. Tumor-targeted IL12 resulted in a marked study explores the identification of neoepitopes in the MC38 increase in clonality of T-cell repertoire infiltrating the colon carcinoma model by comparison of tumor to normal tumor, which when sculpted with the addition of either a DNA and tumor RNA sequencing technology, as well as peptide or adenoviral neoepitope vaccine promoted effi- neoepitope delivery by both peptide- and adenovirus-based cient tumor clearance. In addition, the neoepitope vaccine vaccination strategies. To improve antitumor efficacies, we induced the spread of immunity to neoepitopes expressed combined the vaccine with a group of rationally selected by the tumor but not contained within the vaccine.
    [Show full text]
  • Neoepitopes As Difference Makers for General Cancer Vaccines?
    Author Manuscript Published OnlineFirst on July 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2127 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Neoepitopes as difference makers for general cancer vaccines? Jessica N. Filderman, B.S.1 and Walter J. Storkus, Ph.D.1-5 From the Departments of 1Immunology, 2Dermatology, 3Pathology and 4Bioengineering, University of Pittsburgh School of Medicine and the 5Hillman Cancer Center, Pittsburgh, PA 15213. Correspondence to: Walter J. Storkus, Ph.D. W1151 Biomedical Science Tower Department of Dermatology University of Pittsburgh School of Medicine 200 Lothrop Street Pittsburgh, PA 15213 Tel: 412-648-9981 FAX: 412-383-5857 Email: [email protected] Running Title: Cancer neoepitopes as difference makers (39 characters) Conflicts of Interest: The author has no conflict of interest. Funding: This work was support by NIH T32 CA082084 (JNF) and NIH R01 CA204419 (WJS). Title characters: 61 Text Words: 1,024 Summary Words: 50 References: 5 Figures: 1 1 Downloaded from clincancerres.aacrjournals.org on October 6, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2127 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. SUMMARY: The cancer mutanome has been associated with disease prognosis as well as response to interventional immunotherapy and provides a substrate for development of personalized vaccines targeting tumor neoepitopes. Recent findings suggest that neoantigen-based vaccines may represent general interventional approaches for patients with solid cancers, regardless of their inherent mutational burden.
    [Show full text]
  • (51) International Patent Classification: A61K 39/00 (2006.01) G01N 33/68
    ( (51) International Patent Classification: Published: A61K 39/00 (2006.01) G01N 33/68 (2006.01) — with international search report (Art. 21(3)) G01N 33/574 (2006.01) — before the expiration of the time limit for amending the (21) International Application Number: claims and to be republished in the event of receipt of PCT/EP2020/06 1841 amendments (Rule 48.2(h)) — with sequence listing part of description (Rule 5.2(a)) (22) International Filing Date: 29 April 2020 (29.04.2020) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 19171495.5 29 April 2019 (29.04.2019) EP (71) Applicant: VACCIBODY AS [NO/NO]; Gaustadalleen 21, 0349 Oslo (NO). (72) Inventors: FREDRIKSEN, Agnete, Brunsvik; 0vre Raslingsveg 82b, 2005 Raslingen (NO). SEKELJA, Moni¬ ka; Jarisborgveien li, 0379 Oslo (NO). SCHJETNE, Karoline; Johnsrudgata 48, 1350 Lonunedalen (NO). (74) Agent: H0IBERGP/S; Adelgade 12, 1304 CopenhagenK (DK). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW.
    [Show full text]
  • Population-Level Distribution and Putative Immunogenicity of Cancer Neoepitopes Mary A
    Wood et al. BMC Cancer (2018) 18:414 https://doi.org/10.1186/s12885-018-4325-6 TECHNICAL ADVANCE Open Access Population-level distribution and putative immunogenicity of cancer neoepitopes Mary A. Wood1,2, Mayur Paralkar1,3, Mihir P. Paralkar1,3, Austin Nguyen1,4, Adam J. Struck1, Kyle Ellrott1,5, Adam Margolin1,5, Abhinav Nellore1,5,6 and Reid F. Thompson1,5,7,8* Abstract Background: Tumor neoantigens are drivers of cancer immunotherapy response; however, current prediction tools produce many candidates requiring further prioritization. Additional filtration criteria and population-level understanding may assist with prioritization. Herein, we show neoepitope immunogenicity is related to measures of peptide novelty and report population-level behavior of these and other metrics. Methods: We propose four peptide novelty metrics to refine predicted neoantigenicity: tumor vs. paired normal peptide binding affinity difference, tumor vs. paired normal peptide sequence similarity, tumor vs. closest human peptide sequence similarity, and tumor vs. closest microbial peptide sequence similarity. We apply these metrics to neoepitopes predicted from somatic missense mutations in The Cancer Genome Atlas (TCGA) and a cohort of melanoma patients, and to a group of peptides with neoepitope-specific immune response data using an extension of pVAC-Seq (Hundal et al., pVAC-Seq: a genome-guided in silico approach to identifying tumor neoantigens. Genome Med 8:11, 2016). Results: We show neoepitope burden varies across TCGA diseases and HLA alleles, with surprisingly low repetition of neoepitope sequences across patients or neoepitope preferences among sets of HLA alleles. Only 20.3% of predicted neoepitopes across TCGA patients displayed novel binding change based on our binding affinity difference criteria.
    [Show full text]
  • Identification and Validation of T-Cell Receptors Targeting RAS Hot-Spot Mutations in Human Cancers for Use in Cell-Based Immunotherapy
    Author Manuscript Published OnlineFirst on June 24, 2021; DOI: 10.1158/1078-0432.CCR-21-0849 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Identification and validation of T-cell receptors targeting RAS hot-spot mutations in human cancers for use in cell-based immunotherapy Noam Levin1, Biman C. Paria1, Nolan R Vale1, Rami Yossef1, Frank J. Lowery1, Maria R. 1 1 1 1,2 1 1 Parkhurst , Zhiya Yu , Maria Florentin , Gal Cafri , Jared J. Gartner , Mackenzie L. Shindorf , Lien T. Ngo1, Satyajit Ray1, Sanghyun P. Kim1, Amy R. Copeland1, Paul F. Robbins1, Steven A. Rosenberg1 1 Surgery Branch, National Cancer Institute, Bethesda, Maryland, 20892, USA 2 Sheba Medical Center, Ramat Gan, Israel. Running Title: TCRs recognizing RAS mutations Keywords: T cell, TCR, RAS hotspot mutation Corresponding Author: Steven A. Rosenberg, M.D., Ph.D. 10 Center Drive, Room 3-3940 Bethesda, MD 20892 301-496-4164 [email protected] Conflict of Interest Disclosure Statement: The authors declare no potential conflicts of interest. 1 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 24, 2021; DOI: 10.1158/1078-0432.CCR-21-0849 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Background: Immunotherapies mediate the regression of human tumors through recognition of tumor antigens by immune cells that trigger an immune response. Mutations in the RAS oncogenes occur in about 30% of all cancer patients. These mutations play an important role in both tumor establishment and survival and are commonly found in hotspots.
    [Show full text]
  • Critical Review of Existing MHC I Immunopeptidome Isolation Methods
    molecules Review Critical Review of Existing MHC I Immunopeptidome Isolation Methods Alexandr Kuznetsov 1, Alice Voronina 1 , Vadim Govorun 1,2 and Georgij Arapidi 2,3,4,* 1 Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia; [email protected] (A.K.); [email protected] (A.V.); [email protected] (V.G.) 2 Department of Molecular and Translational Medicine, Moscow Institute of Physics and Technology (State University), 141701 Dolgoprudny, Russia 3 Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia 4 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 117997 Moscow, Russia * Correspondence: [email protected]; Tel.: +7-926-471-1420 Academic Editor: Luca D. D’Andrea Received: 5 October 2020; Accepted: 17 November 2020; Published: 19 November 2020 Abstract: Major histocompatibility complex class I (MHC I) plays a crucial role in the development of adaptive immune response in vertebrates. MHC molecules are cell surface protein complexes loaded with short peptides and recognized by the T-cell receptors (TCR). Peptides associated with MHC are named immunopeptidome. The MHC I immunopeptidome is produced by the proteasome degradation of intracellular proteins. The knowledge of the immunopeptidome repertoire facilitates the creation of personalized antitumor or antiviral vaccines. A huge number of publications on the immunopeptidome diversity of different human and mouse biological samples—plasma, peripheral blood mononuclear cells (PBMCs), and solid tissues, including tumors—appeared in the scientific journals in the last decade.
    [Show full text]
  • Immunitybio and Nantomics Announce Clinical Validation of a Proprietary Method to Identify Unique Targets for Immunotherapy in Individual Breast Cancer Patients
    ImmunityBio and NantOmics Announce Clinical Validation of a Proprietary Method to Identify Unique Targets for Immunotherapy in Individual Breast Cancer Patients June 28, 2021 The “neoepitope” identification pipeline facilitates discovery of immunotherapy targets unique to individual cancer patients as a personalized and precision medicine approach to treatment The neoepitopes identified can be leveraged to improve outcomes with adoptive cell transfer therapy and personalized vaccines Adenovirus and Yeast vaccine platforms in Phase1/2 clinical trials to drive immunity to tumor-associated antigens and neoantigens across multiple solid tumor types CULVER CITY, Calif.--(BUSINESS WIRE)--Jun. 28, 2021-- ImmunityBio, Inc. (NASDAQ: IBRX), a publicly traded immunotherapy company , and privately-held NantOmics today announced publication of a stepwise approach or “pipeline” for identification and validation of neoepitope and neoepitope-reactive T cells from individual patients. The identification of neoepitopes—short peptide sequences that are mutated in tumors and are capable of generating an immune response—provides critical support in the successful development of next-generation immunotherapies delivered by ImmunityBio’s Adeno- and yeast-based platforms. The pipeline is described in “Identification and validation of expressed HLA-binding breast cancer neoepitopes for potential use in individualized cancer therapy,” which recently published in the Journal for Immunotherapy of Cancer. The pipeline leverages the bioinformatics capabilities of NantOmics and ImmunityBio to predict neoepitopes based on genomic and expression analyses that have a high likelihood of generating a tumor-fighting immune response and the generation of neoepitope-specific CD4+ and CD8+ T cells when delivered using the Adeno and yeast vaccine platforms. These predicted neoepitopes once identified are synthesized as short peptides, and run through a series of studies to confirm their potential utility in the cancer vaccine platforms.
    [Show full text]
  • Unique Genomic and Neoepitope Landscapes Across Tumors: a Study Across Time, Tissues, and Space Within a Single Lynch Syndrome Patient Tanya N
    www.nature.com/scientificreports OPEN Unique genomic and neoepitope landscapes across tumors: a study across time, tissues, and space within a single lynch syndrome patient Tanya N. Phung1,2, Elizabeth Lenkiewicz3, Smriti Malasi3, Amit Sharma4, Karen S. Anderson1,3,4, Melissa A. Wilson1,2,4, Barbara A. Pockaj5 & Michael T. Barrett3* Lynch syndrome (LS) arises in patients with pathogenic germline variants in DNA mismatch repair genes. LS is the most common inherited cancer predisposition condition and confers an elevated lifetime risk of multiple cancers notably colorectal and endometrial carcinomas. A distinguishing feature of LS associated tumors is accumulation of variants targeting microsatellite repeats and the potential for high tumor specifc neoepitope levels. Recurrent somatic variants targeting a small subset of genes have been identifed in tumors with microsatellite instability. Notably these include frameshifts that can activate immune responses and provide vaccine targets to afect the lifetime cancer risk associated with LS. However the presence and persistence of targeted neoepitopes across multiple tumors in single LS patients has not been rigorously studied. Here we profled the genomic landscapes of fve distinct treatment naïve tumors, a papillary transitional cell renal cell carcinoma, a duodenal carcinoma, two metachronous colorectal carcinomas, and multi-regional sampling in a triple-negative breast tumor, arising in a LS patient over 10 years. Our analyses suggest each tumor evolves a unique complement of variants and that vaccines based on potential neoepitopes from one tissue may not be efective across all tumors that can arise during the lifetime of LS patients. Lynch syndrome (LS) is the most common human cancer predisposition syndrome 1.
    [Show full text]
  • HLA-Binding Properties of Tumor Neoepitopes in Humans
    Published OnlineFirst March 3, 2014; DOI: 10.1158/2326-6066.CIR-13-0227 Cancer Immunology Cancer Immunology Miniatures Research See related commentary by Lutz and Jaffee, p. 518 HLA-Binding Properties of Tumor Neoepitopes in Humans Edward F. Fritsch1,2,5, Mohini Rajasagi1,2, Patrick A. Ott2,4, Vladimir Brusic1,4, Nir Hacohen3,5, and Catherine J. Wu1,2,4 Abstract Cancer genome sequencing has enabled the rapid identification of the complete repertoire of coding sequence mutations within a patient's tumor and facilitated their use as personalized immunogens. Although a variety of techniques are available to assist in the selection of mutation-defined epitopes to be included within the tumor vaccine, the ability of the peptide to bind to patient MHC is a key gateway to peptide presentation. With advances in the accuracy of predictive algorithms for MHC class I binding, choosing epitopes on the basis of predicted affinity provides a rapid and unbiased approach to epitope prioritization. We show herein the retrospective application of a prediction algorithm to a large set of bona fide T cell–defined mutated human tumor antigens that induced immune responses, most of which were associated with tumor regression or long- term disease stability. The results support the application of this approach for epitope selection and reveal informative features of these naturally occurring epitopes to aid in epitope prioritization for use in tumor vaccines. Cancer Immunol Res; 2(6); 522–9. Ó2014 AACR. Introduction drowned out within the vast sea of immunologically irrelevant We and others (1–3) have suggested that the vast number of antigens.
    [Show full text]
  • Characterization of Neoantigen-Specific T Cells in Cancer Resistant to Immune Checkpoint Therapies
    Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies Shamin Lia,1, Yannick Simonia,b, Summer Zhuanga, Austin Gabelc,d,e,f, Shaokang Mag, Jonathan Cheeg, Laura Islasa, Anthony Cessnaa, Jenette Creaneyg,h,i, Robert K. Bradleyc,d,e, Alec Redwoodg, Bruce W. Robinsong, and Evan W. Newella,1 aVaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; bImmunoSCAPE, Pte Ltd, Singapore, 228208 Singapore; cComputational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; dBasic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; eDepartment of Genome Sciences, University of Washington, Seattle, WA 98195; fMedical Scientist Training Program, University of Washington, Seattle, WA 98195; gNational Centre for Asbestos Related Disease, Faculty of Health and Medical Science, University of Western Australia, 6009 Perth, Australia; hDepartment of Respiratory Medicine, Sir Charles Gairdner Hospital, 6009 Perth, Australia; and iInstitute for Respiratory Health, University of Western Australia, 6009 Perth, Australia Edited by Rafi Ahmed, Emory University, Atlanta, GA, and approved June 16, 2021 (received for review December 14, 2020) Neoantigen-specific T cells are strongly implicated as being critical for (MCA) sarcoma for instance, two immunodominant neoantigens effective immune checkpoint blockade treatment (ICB) (e.g., anti–PD-1 have been identified and showed to be reactivated upon anti–PD-1 and anti–CTLA-4) and are being targeted for vaccination-based thera- and/or anti–CTLA-4 blockade, enabling an effective tumor rejec- pies. However, ICB treatments show uneven responses between pa- tion that could be boosted via neopeptide-based vaccination (21).
    [Show full text]
  • T Cell Neoepitope Discovery in Colorectal Cancer by High
    GI cancer ORIGINAL ARTICLE Gut: first published as 10.1136/gutjnl-2015-309453 on 17 December 2015. Downloaded from T cell neoepitope discovery in colorectal cancer by high throughput profiling of somatic mutations in expressed genes Daniele Mennonna,1 Cristina Maccalli,2 Michele C Romano,1 Claudio Garavaglia,1 Filippo Capocefalo,2 Roberta Bordoni,3 Marco Severgnini,3 Gianluca De Bellis,3 John Sidney,4 Alessandro Sette,4 Alessandro Gori,5 Renato Longhi,5 Marco Braga,6 Luca Ghirardelli,6 Ludovica Baldari,6 Elena Orsenigo,6 Luca Albarello,7 Elisabetta Zino,8 Katharina Fleischhauer,8,9 Gina Mazzola,10 Norma Ferrero,10 Antonio Amoroso,10 Giulia Casorati,1 Giorgio Parmiani,2 Paolo Dellabona1 ▸ Additional material is ABSTRACT published online only. To view Objective Patient-specific (unique) tumour antigens, Significance of this study these files please visit the journal online (http://dx.doi. encoded by somatically mutated cancer genes, generate org/10.1136/gutjnl-2015- neoepitopes that are implicated in the induction of 309453). tumour-controlling T cell responses. Recent What is already known on this subject? advancements in massive DNA sequencing combined ▸ It is now well established that T lymphocytes fi with robust T cell epitope predictions have allowed their play a critical role in controlling cancer For numbered af liations see fi end of article. systematic identi cation in several malignancies. progression. Design We undertook the identification of unique ▸ T lymphocytes recognised peptides, called Correspondence to neoepitopes in colorectal cancers (CRCs) by using high- epitopes, derived from tumour associated Dr Paolo Dellabona, Division of throughput sequencing of cDNAs expressed by standard protein antigens.
    [Show full text]