Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy.
Identifieur interne : 000178 ( France/Analysis ); précédent : 000177; suivant : 000179Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy.
Auteurs : Pauline Maby [France] ; David Tougeron [France] ; Mohamad Hamieh [France] ; Bernhard Mlecnik [France] ; Hafid Kora [France] ; Gabriela Bindea [France] ; Helen K. Angell [Royaume-Uni] ; Tessa Fredriksen [France] ; Nicolas Elie [France] ; Emilie Fauquembergue [France] ; Aurélie Drouet [France] ; Jérôme Leprince [France] ; Jacques Benichou [France] ; Jacques Mauillon [France] ; Florence Le Pessot [France] ; Richard Sesboüé [France] ; Jean-Jacques Tuech [France] ; Jean-Christophe Sabourin [France] ; Pierre Michel [France] ; Thierry Frébourg [France] ; Jérôme Galon [France] ; Jean-Baptiste Latouche [France]Source :
- Cancer research [ 1538-7445 ] ; 2015.
English descriptors
- KwdEn :
- Antigen-Presenting Cells (immunology), CD8-Positive T-Lymphocytes (immunology), CD8-Positive T-Lymphocytes (pathology), Colorectal Neoplasms (genetics), Colorectal Neoplasms (immunology), Colorectal Neoplasms (pathology), Colorectal Neoplasms, Hereditary Nonpolyposis (genetics), Colorectal Neoplasms, Hereditary Nonpolyposis (immunology), Colorectal Neoplasms, Hereditary Nonpolyposis (pathology), Female, Forkhead Transcription Factors (genetics), Frameshift Mutation (genetics), Humans, Immunotherapy, Lymphocytes, Tumor-Infiltrating (immunology), Lymphocytes, Tumor-Infiltrating (pathology), Male, Microsatellite Instability, Precision Medicine.
- MESH :
- chemical , genetics : Forkhead Transcription Factors.
- genetics : Colorectal Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, Frameshift Mutation.
- immunology : Antigen-Presenting Cells, CD8-Positive T-Lymphocytes, Colorectal Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, Lymphocytes, Tumor-Infiltrating.
- pathology : CD8-Positive T-Lymphocytes, Colorectal Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, Lymphocytes, Tumor-Infiltrating.
- Female, Humans, Immunotherapy, Male, Microsatellite Instability, Precision Medicine.
Abstract
Colorectal cancers with microsatellite instability (MSI) represent 15% of all colorectal cancers, including Lynch syndrome as the most frequent hereditary form of this disease. Notably, MSI colorectal cancers have a higher density of tumor-infiltrating lymphocytes (TIL) than other colorectal cancers. This feature is thought to reflect the accumulation of frameshift mutations in sequences that are repeated within gene coding regions, thereby leading to the synthesis of neoantigens recognized by CD8(+) T cells. However, there has yet to be a clear link established between CD8(+) TIL density and frameshift mutations in colorectal cancer. In this study, we examined this link in 103 MSI colorectal cancers from two independent cohorts where frameshift mutations in 19 genes were analyzed and CD3(+), CD8(+), and FOXP3(+) TIL densities were quantitated. We found that CD8(+) TIL density correlated positively with the total number of frameshift mutations. TIL densities increased when frameshift mutations were present within the ASTE1, HNF1A, or TCF7L2 genes, increasing even further when at least one of these frameshift mutations was present in all tumor cells. Through in vitro assays using engineered antigen-presenting cells, we were able to stimulate peripheral cytotoxic T cells obtained from colorectal cancer patients with peptides derived from frameshift mutations found in their tumors. Taken together, our results highlight the importance of a CD8(+) T cell immune response against MSI colorectal cancer-specific neoantigens, establishing a preclinical rationale to target them as a personalized cellular immunotherapy strategy, an especially appealing goal for patients with Lynch syndrome.
DOI: 10.1158/0008-5472.CAN-14-3051
PubMed: 26060019
Affiliations:
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pubmed:26060019Le document en format XML
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Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. 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Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Angell, Helen K" sort="Angell, Helen K" uniqKey="Angell H" first="Helen K" last="Angell">Helen K. Angell</name><affiliation wicri:level="4"><nlm:affiliation>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France. AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France. AstraZeneca Pharmaceuticals, Alderley Park, Cheshire</wicri:regionArea><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Fredriksen, Tessa" sort="Fredriksen, Tessa" uniqKey="Fredriksen T" first="Tessa" last="Fredriksen">Tessa Fredriksen</name><affiliation wicri:level="4"><nlm:affiliation>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Elie, Nicolas" sort="Elie, Nicolas" uniqKey="Elie N" first="Nicolas" last="Elie">Nicolas Elie</name><affiliation wicri:level="1"><nlm:affiliation>Imaging Core Facility, CMABIO, Caen University Hospital, Caen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Imaging Core Facility, CMABIO, Caen University Hospital, Caen</wicri:regionArea><placeName><settlement type="city">Caen</settlement></placeName></affiliation></author><author><name sortKey="Fauquembergue, Emilie" sort="Fauquembergue, Emilie" uniqKey="Fauquembergue E" first="Emilie" last="Fauquembergue">Emilie Fauquembergue</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Drouet, Aurelie" sort="Drouet, Aurelie" uniqKey="Drouet A" first="Aurélie" last="Drouet">Aurélie Drouet</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Leprince, Jerome" sort="Leprince, Jerome" uniqKey="Leprince J" first="Jérôme" last="Leprince">Jérôme Leprince</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U982, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U982, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University</wicri:regionArea><wicri:noRegion>Rouen University</wicri:noRegion><wicri:noRegion>Rouen University</wicri:noRegion></affiliation></author><author><name sortKey="Benichou, Jacques" sort="Benichou, Jacques" uniqKey="Benichou J" first="Jacques" last="Benichou">Jacques Benichou</name><affiliation wicri:level="1"><nlm:affiliation>Biostatistics Unit, Inserm U657, Rouen University Hospital, Rouen University, Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Biostatistics Unit, Inserm U657, Rouen University Hospital, Rouen University, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Mauillon, Jacques" sort="Mauillon, Jacques" uniqKey="Mauillon J" first="Jacques" last="Mauillon">Jacques Mauillon</name><affiliation wicri:level="1"><nlm:affiliation>Department of Genetics, Rouen University Hospital, Rouen, France. Department of Gastroenterology, Le Havre Hospital, Le Havre, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Genetics, Rouen University Hospital, Rouen, France. Department of Gastroenterology, Le Havre Hospital, Le Havre</wicri:regionArea><placeName><settlement type="city">Le Havre</settlement></placeName></affiliation></author><author><name sortKey="Le Pessot, Florence" sort="Le Pessot, Florence" uniqKey="Le Pessot F" first="Florence" last="Le Pessot">Florence Le Pessot</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Rouen University Hospital, Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Pathology, Rouen University Hospital, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Sesboue, Richard" sort="Sesboue, Richard" uniqKey="Sesboue R" first="Richard" last="Sesboüé">Richard Sesboüé</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Tuech, Jean Jacques" sort="Tuech, Jean Jacques" uniqKey="Tuech J" first="Jean-Jacques" last="Tuech">Jean-Jacques Tuech</name><affiliation wicri:level="1"><nlm:affiliation>Department of Digestive Surgery, Rouen University Hospital, Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Digestive Surgery, Rouen University Hospital, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Sabourin, Jean Christophe" sort="Sabourin, Jean Christophe" uniqKey="Sabourin J" first="Jean-Christophe" last="Sabourin">Jean-Christophe Sabourin</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Pathology, Rouen University Hospital, Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Pathology, Rouen University Hospital, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Michel, Pierre" sort="Michel, Pierre" uniqKey="Michel P" first="Pierre" last="Michel">Pierre Michel</name><affiliation wicri:level="1"><nlm:affiliation>Department of Gastroenterology, Rouen University Hospital, Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Gastroenterology, Rouen University Hospital, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Frebourg, Thierry" sort="Frebourg, Thierry" uniqKey="Frebourg T" first="Thierry" last="Frébourg">Thierry Frébourg</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Galon, Jerome" sort="Galon, Jerome" uniqKey="Galon J" first="Jérôme" last="Galon">Jérôme Galon</name><affiliation wicri:level="4"><nlm:affiliation>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Latouche, Jean Baptiste" sort="Latouche, Jean Baptiste" uniqKey="Latouche J" first="Jean-Baptiste" last="Latouche">Jean-Baptiste Latouche</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen, France. jean-baptiste.latouche@chu-rouen.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:26060019</idno><idno type="pmid">26060019</idno><idno type="doi">10.1158/0008-5472.CAN-14-3051</idno><idno type="wicri:Area/PubMed/Corpus">000069</idno><idno type="wicri:Area/PubMed/Curation">000069</idno><idno type="wicri:Area/PubMed/Checkpoint">000069</idno><idno type="wicri:Area/Ncbi/Merge">000477</idno><idno type="wicri:Area/Ncbi/Curation">000477</idno><idno type="wicri:Area/Ncbi/Checkpoint">000477</idno><idno type="wicri:Area/Main/Merge">000186</idno><idno type="wicri:Area/Main/Curation">000188</idno><idno type="wicri:Area/Main/Exploration">000188</idno><idno type="wicri:Area/France/Extraction">000178</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy.</title><author><name sortKey="Maby, Pauline" sort="Maby, Pauline" uniqKey="Maby P" first="Pauline" last="Maby">Pauline Maby</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Tougeron, David" sort="Tougeron, David" uniqKey="Tougeron D" first="David" last="Tougeron">David Tougeron</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Gastroenterology, Poitiers University Hospital, Poitiers, France. Laboratoire Inflammation Tissus Epithéliaux et Cytokines, Poitiers University, Poitiers, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Gastroenterology, Poitiers University Hospital, Poitiers, France. Laboratoire Inflammation Tissus Epithéliaux et Cytokines, Poitiers University, Poitiers</wicri:regionArea><placeName><settlement type="city">Poitiers</settlement></placeName></affiliation></author><author><name sortKey="Hamieh, Mohamad" sort="Hamieh, Mohamad" uniqKey="Hamieh M" first="Mohamad" last="Hamieh">Mohamad Hamieh</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Mlecnik, Bernhard" sort="Mlecnik, Bernhard" uniqKey="Mlecnik B" first="Bernhard" last="Mlecnik">Bernhard Mlecnik</name><affiliation wicri:level="4"><nlm:affiliation>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Kora, Hafid" sort="Kora, Hafid" uniqKey="Kora H" first="Hafid" last="Kora">Hafid Kora</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Bindea, Gabriela" sort="Bindea, Gabriela" uniqKey="Bindea G" first="Gabriela" last="Bindea">Gabriela Bindea</name><affiliation wicri:level="4"><nlm:affiliation>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Angell, Helen K" sort="Angell, Helen K" uniqKey="Angell H" first="Helen K" last="Angell">Helen K. Angell</name><affiliation wicri:level="4"><nlm:affiliation>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France. AstraZeneca Pharmaceuticals, Alderley Park, Cheshire, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France. AstraZeneca Pharmaceuticals, Alderley Park, Cheshire</wicri:regionArea><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Fredriksen, Tessa" sort="Fredriksen, Tessa" uniqKey="Fredriksen T" first="Tessa" last="Fredriksen">Tessa Fredriksen</name><affiliation wicri:level="4"><nlm:affiliation>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Elie, Nicolas" sort="Elie, Nicolas" uniqKey="Elie N" first="Nicolas" last="Elie">Nicolas Elie</name><affiliation wicri:level="1"><nlm:affiliation>Imaging Core Facility, CMABIO, Caen University Hospital, Caen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Imaging Core Facility, CMABIO, Caen University Hospital, Caen</wicri:regionArea><placeName><settlement type="city">Caen</settlement></placeName></affiliation></author><author><name sortKey="Fauquembergue, Emilie" sort="Fauquembergue, Emilie" uniqKey="Fauquembergue E" first="Emilie" last="Fauquembergue">Emilie Fauquembergue</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Drouet, Aurelie" sort="Drouet, Aurelie" uniqKey="Drouet A" first="Aurélie" last="Drouet">Aurélie Drouet</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Leprince, Jerome" sort="Leprince, Jerome" uniqKey="Leprince J" first="Jérôme" last="Leprince">Jérôme Leprince</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U982, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U982, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University</wicri:regionArea><wicri:noRegion>Rouen University</wicri:noRegion><wicri:noRegion>Rouen University</wicri:noRegion></affiliation></author><author><name sortKey="Benichou, Jacques" sort="Benichou, Jacques" uniqKey="Benichou J" first="Jacques" last="Benichou">Jacques Benichou</name><affiliation wicri:level="1"><nlm:affiliation>Biostatistics Unit, Inserm U657, Rouen University Hospital, Rouen University, Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Biostatistics Unit, Inserm U657, Rouen University Hospital, Rouen University, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Mauillon, Jacques" sort="Mauillon, Jacques" uniqKey="Mauillon J" first="Jacques" last="Mauillon">Jacques Mauillon</name><affiliation wicri:level="1"><nlm:affiliation>Department of Genetics, Rouen University Hospital, Rouen, France. Department of Gastroenterology, Le Havre Hospital, Le Havre, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Genetics, Rouen University Hospital, Rouen, France. Department of Gastroenterology, Le Havre Hospital, Le Havre</wicri:regionArea><placeName><settlement type="city">Le Havre</settlement></placeName></affiliation></author><author><name sortKey="Le Pessot, Florence" sort="Le Pessot, Florence" uniqKey="Le Pessot F" first="Florence" last="Le Pessot">Florence Le Pessot</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Rouen University Hospital, Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Pathology, Rouen University Hospital, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Sesboue, Richard" sort="Sesboue, Richard" uniqKey="Sesboue R" first="Richard" last="Sesboüé">Richard Sesboüé</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Tuech, Jean Jacques" sort="Tuech, Jean Jacques" uniqKey="Tuech J" first="Jean-Jacques" last="Tuech">Jean-Jacques Tuech</name><affiliation wicri:level="1"><nlm:affiliation>Department of Digestive Surgery, Rouen University Hospital, Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Digestive Surgery, Rouen University Hospital, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Sabourin, Jean Christophe" sort="Sabourin, Jean Christophe" uniqKey="Sabourin J" first="Jean-Christophe" last="Sabourin">Jean-Christophe Sabourin</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Pathology, Rouen University Hospital, Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Pathology, Rouen University Hospital, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Michel, Pierre" sort="Michel, Pierre" uniqKey="Michel P" first="Pierre" last="Michel">Pierre Michel</name><affiliation wicri:level="1"><nlm:affiliation>Department of Gastroenterology, Rouen University Hospital, Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Department of Gastroenterology, Rouen University Hospital, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Frebourg, Thierry" sort="Frebourg, Thierry" uniqKey="Frebourg T" first="Thierry" last="Frébourg">Thierry Frébourg</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author><author><name sortKey="Galon, Jerome" sort="Galon, Jerome" uniqKey="Galon J" first="Jérôme" last="Galon">Jérôme Galon</name><affiliation wicri:level="4"><nlm:affiliation>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1138, Laboratory of Integrative Cancer Immunology, Paris, France. Université Paris Descartes, Paris, France. Cordeliers Research Centre, Université Pierre et Marie Curie, Paris 6, Paris</wicri:regionArea><placeName><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris Descartes</orgName><placeName><settlement type="city">Paris</settlement><region type="region" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Latouche, Jean Baptiste" sort="Latouche, Jean Baptiste" uniqKey="Latouche J" first="Jean-Baptiste" last="Latouche">Jean-Baptiste Latouche</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen, France. jean-baptiste.latouche@chu-rouen.fr.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen</wicri:regionArea><placeName><settlement type="city">Rouen</settlement></placeName></affiliation></author></analytic><series><title level="j">Cancer research</title><idno type="eISSN">1538-7445</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antigen-Presenting Cells (immunology)</term><term>CD8-Positive T-Lymphocytes (immunology)</term><term>CD8-Positive T-Lymphocytes (pathology)</term><term>Colorectal Neoplasms (genetics)</term><term>Colorectal Neoplasms (immunology)</term><term>Colorectal Neoplasms (pathology)</term><term>Colorectal Neoplasms, Hereditary Nonpolyposis (genetics)</term><term>Colorectal Neoplasms, Hereditary Nonpolyposis (immunology)</term><term>Colorectal Neoplasms, Hereditary Nonpolyposis (pathology)</term><term>Female</term><term>Forkhead Transcription Factors (genetics)</term><term>Frameshift Mutation (genetics)</term><term>Humans</term><term>Immunotherapy</term><term>Lymphocytes, Tumor-Infiltrating (immunology)</term><term>Lymphocytes, Tumor-Infiltrating (pathology)</term><term>Male</term><term>Microsatellite Instability</term><term>Precision Medicine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Forkhead Transcription Factors</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Colorectal Neoplasms</term><term>Colorectal Neoplasms, Hereditary Nonpolyposis</term><term>Frameshift Mutation</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Antigen-Presenting Cells</term><term>CD8-Positive T-Lymphocytes</term><term>Colorectal Neoplasms</term><term>Colorectal Neoplasms, Hereditary Nonpolyposis</term><term>Lymphocytes, Tumor-Infiltrating</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>CD8-Positive T-Lymphocytes</term><term>Colorectal Neoplasms</term><term>Colorectal Neoplasms, Hereditary Nonpolyposis</term><term>Lymphocytes, Tumor-Infiltrating</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Female</term><term>Humans</term><term>Immunotherapy</term><term>Male</term><term>Microsatellite Instability</term><term>Precision Medicine</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Colorectal cancers with microsatellite instability (MSI) represent 15% of all colorectal cancers, including Lynch syndrome as the most frequent hereditary form of this disease. Notably, MSI colorectal cancers have a higher density of tumor-infiltrating lymphocytes (TIL) than other colorectal cancers. This feature is thought to reflect the accumulation of frameshift mutations in sequences that are repeated within gene coding regions, thereby leading to the synthesis of neoantigens recognized by CD8(+) T cells. However, there has yet to be a clear link established between CD8(+) TIL density and frameshift mutations in colorectal cancer. In this study, we examined this link in 103 MSI colorectal cancers from two independent cohorts where frameshift mutations in 19 genes were analyzed and CD3(+), CD8(+), and FOXP3(+) TIL densities were quantitated. We found that CD8(+) TIL density correlated positively with the total number of frameshift mutations. TIL densities increased when frameshift mutations were present within the ASTE1, HNF1A, or TCF7L2 genes, increasing even further when at least one of these frameshift mutations was present in all tumor cells. Through in vitro assays using engineered antigen-presenting cells, we were able to stimulate peripheral cytotoxic T cells obtained from colorectal cancer patients with peptides derived from frameshift mutations found in their tumors. Taken together, our results highlight the importance of a CD8(+) T cell immune response against MSI colorectal cancer-specific neoantigens, establishing a preclinical rationale to target them as a personalized cellular immunotherapy strategy, an especially appealing goal for patients with Lynch syndrome.</div></front></TEI><affiliations><list><country><li>France</li><li>Royaume-Uni</li></country><region><li>Île-de-France</li></region><settlement><li>Caen</li><li>Le Havre</li><li>Paris</li><li>Poitiers</li><li>Rouen</li></settlement><orgName><li>Université Paris Descartes</li></orgName></list><tree><country name="France"><noRegion><name sortKey="Maby, Pauline" sort="Maby, Pauline" uniqKey="Maby P" first="Pauline" last="Maby">Pauline Maby</name></noRegion><name sortKey="Benichou, Jacques" sort="Benichou, Jacques" uniqKey="Benichou J" first="Jacques" last="Benichou">Jacques Benichou</name><name sortKey="Bindea, Gabriela" sort="Bindea, Gabriela" uniqKey="Bindea G" first="Gabriela" last="Bindea">Gabriela Bindea</name><name sortKey="Drouet, Aurelie" sort="Drouet, Aurelie" uniqKey="Drouet A" first="Aurélie" last="Drouet">Aurélie Drouet</name><name sortKey="Elie, Nicolas" sort="Elie, Nicolas" uniqKey="Elie N" first="Nicolas" last="Elie">Nicolas Elie</name><name sortKey="Fauquembergue, Emilie" sort="Fauquembergue, Emilie" uniqKey="Fauquembergue E" first="Emilie" last="Fauquembergue">Emilie Fauquembergue</name><name sortKey="Frebourg, Thierry" sort="Frebourg, Thierry" uniqKey="Frebourg T" first="Thierry" last="Frébourg">Thierry Frébourg</name><name sortKey="Fredriksen, Tessa" sort="Fredriksen, Tessa" uniqKey="Fredriksen T" first="Tessa" last="Fredriksen">Tessa Fredriksen</name><name sortKey="Galon, Jerome" sort="Galon, Jerome" uniqKey="Galon J" first="Jérôme" last="Galon">Jérôme Galon</name><name sortKey="Hamieh, Mohamad" sort="Hamieh, Mohamad" uniqKey="Hamieh M" first="Mohamad" last="Hamieh">Mohamad Hamieh</name><name sortKey="Kora, Hafid" sort="Kora, Hafid" uniqKey="Kora H" first="Hafid" last="Kora">Hafid Kora</name><name sortKey="Latouche, Jean Baptiste" sort="Latouche, Jean Baptiste" uniqKey="Latouche J" first="Jean-Baptiste" last="Latouche">Jean-Baptiste Latouche</name><name sortKey="Le Pessot, Florence" sort="Le Pessot, Florence" uniqKey="Le Pessot F" first="Florence" last="Le Pessot">Florence Le Pessot</name><name sortKey="Leprince, Jerome" sort="Leprince, Jerome" uniqKey="Leprince J" first="Jérôme" last="Leprince">Jérôme Leprince</name><name sortKey="Mauillon, Jacques" sort="Mauillon, Jacques" uniqKey="Mauillon J" first="Jacques" last="Mauillon">Jacques Mauillon</name><name sortKey="Michel, Pierre" sort="Michel, Pierre" uniqKey="Michel P" first="Pierre" last="Michel">Pierre Michel</name><name sortKey="Mlecnik, Bernhard" sort="Mlecnik, Bernhard" uniqKey="Mlecnik B" first="Bernhard" last="Mlecnik">Bernhard Mlecnik</name><name sortKey="Sabourin, Jean Christophe" sort="Sabourin, Jean Christophe" uniqKey="Sabourin J" first="Jean-Christophe" last="Sabourin">Jean-Christophe Sabourin</name><name sortKey="Sesboue, Richard" sort="Sesboue, Richard" uniqKey="Sesboue R" first="Richard" last="Sesboüé">Richard Sesboüé</name><name sortKey="Tougeron, David" sort="Tougeron, David" uniqKey="Tougeron D" first="David" last="Tougeron">David Tougeron</name><name sortKey="Tuech, Jean Jacques" sort="Tuech, Jean Jacques" uniqKey="Tuech J" first="Jean-Jacques" last="Tuech">Jean-Jacques Tuech</name></country><country name="Royaume-Uni"><region name="Île-de-France"><name sortKey="Angell, Helen K" sort="Angell, Helen K" uniqKey="Angell H" first="Helen K" last="Angell">Helen K. 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