Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy.
Identifieur interne : 000069 ( PubMed/Corpus ); précédent : 000068; suivant : 000070Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy.
Auteurs : Pauline Maby ; David Tougeron ; Mohamad Hamieh ; Bernhard Mlecnik ; Hafid Kora ; Gabriela Bindea ; Helen K. Angell ; Tessa Fredriksen ; Nicolas Elie ; Emilie Fauquembergue ; Aurélie Drouet ; Jérôme Leprince ; Jacques Benichou ; Jacques Mauillon ; Florence Le Pessot ; Richard Sesboüé ; Jean-Jacques Tuech ; Jean-Christophe Sabourin ; Pierre Michel ; Thierry Frébourg ; Jérôme Galon ; Jean-Baptiste LatoucheSource :
- 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
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pubmed:26060019Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><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><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Tougeron, David" sort="Tougeron, David" uniqKey="Tougeron D" first="David" last="Tougeron">David Tougeron</name><affiliation><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></affiliation></author><author><name sortKey="Hamieh, Mohamad" sort="Hamieh, Mohamad" uniqKey="Hamieh M" first="Mohamad" last="Hamieh">Mohamad Hamieh</name><affiliation><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Mlecnik, Bernhard" sort="Mlecnik, Bernhard" uniqKey="Mlecnik B" first="Bernhard" last="Mlecnik">Bernhard Mlecnik</name><affiliation><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></affiliation></author><author><name sortKey="Kora, Hafid" sort="Kora, Hafid" uniqKey="Kora H" first="Hafid" last="Kora">Hafid Kora</name><affiliation><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Bindea, Gabriela" sort="Bindea, Gabriela" uniqKey="Bindea G" first="Gabriela" last="Bindea">Gabriela Bindea</name><affiliation><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></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><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></affiliation></author><author><name sortKey="Fredriksen, Tessa" sort="Fredriksen, Tessa" uniqKey="Fredriksen T" first="Tessa" last="Fredriksen">Tessa Fredriksen</name><affiliation><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></affiliation></author><author><name sortKey="Elie, Nicolas" sort="Elie, Nicolas" uniqKey="Elie N" first="Nicolas" last="Elie">Nicolas Elie</name><affiliation><nlm:affiliation>Imaging Core Facility, CMABIO, Caen University Hospital, Caen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Fauquembergue, Emilie" sort="Fauquembergue, Emilie" uniqKey="Fauquembergue E" first="Emilie" last="Fauquembergue">Emilie Fauquembergue</name><affiliation><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Drouet, Aurelie" sort="Drouet, Aurelie" uniqKey="Drouet A" first="Aurélie" last="Drouet">Aurélie Drouet</name><affiliation><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Leprince, Jerome" sort="Leprince, Jerome" uniqKey="Leprince J" first="Jérôme" last="Leprince">Jérôme Leprince</name><affiliation><nlm:affiliation>Inserm U982, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, France.</nlm:affiliation></affiliation></author><author><name sortKey="Benichou, Jacques" sort="Benichou, Jacques" uniqKey="Benichou J" first="Jacques" last="Benichou">Jacques Benichou</name><affiliation><nlm:affiliation>Biostatistics Unit, Inserm U657, Rouen University Hospital, Rouen University, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Mauillon, Jacques" sort="Mauillon, Jacques" uniqKey="Mauillon J" first="Jacques" last="Mauillon">Jacques Mauillon</name><affiliation><nlm:affiliation>Department of Genetics, Rouen University Hospital, Rouen, France. Department of Gastroenterology, Le Havre Hospital, Le Havre, France.</nlm:affiliation></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><nlm:affiliation>Department of Pathology, Rouen University Hospital, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Sesboue, Richard" sort="Sesboue, Richard" uniqKey="Sesboue R" first="Richard" last="Sesboüé">Richard Sesboüé</name><affiliation><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation></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><nlm:affiliation>Department of Digestive Surgery, Rouen University Hospital, Rouen, France.</nlm:affiliation></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><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Pathology, Rouen University Hospital, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Michel, Pierre" sort="Michel, Pierre" uniqKey="Michel P" first="Pierre" last="Michel">Pierre Michel</name><affiliation><nlm:affiliation>Department of Gastroenterology, Rouen University Hospital, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Frebourg, Thierry" sort="Frebourg, Thierry" uniqKey="Frebourg T" first="Thierry" last="Frébourg">Thierry Frébourg</name><affiliation><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Galon, Jerome" sort="Galon, Jerome" uniqKey="Galon J" first="Jérôme" last="Galon">Jérôme Galon</name><affiliation><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></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><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></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></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><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Tougeron, David" sort="Tougeron, David" uniqKey="Tougeron D" first="David" last="Tougeron">David Tougeron</name><affiliation><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></affiliation></author><author><name sortKey="Hamieh, Mohamad" sort="Hamieh, Mohamad" uniqKey="Hamieh M" first="Mohamad" last="Hamieh">Mohamad Hamieh</name><affiliation><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Mlecnik, Bernhard" sort="Mlecnik, Bernhard" uniqKey="Mlecnik B" first="Bernhard" last="Mlecnik">Bernhard Mlecnik</name><affiliation><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></affiliation></author><author><name sortKey="Kora, Hafid" sort="Kora, Hafid" uniqKey="Kora H" first="Hafid" last="Kora">Hafid Kora</name><affiliation><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Bindea, Gabriela" sort="Bindea, Gabriela" uniqKey="Bindea G" first="Gabriela" last="Bindea">Gabriela Bindea</name><affiliation><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></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><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></affiliation></author><author><name sortKey="Fredriksen, Tessa" sort="Fredriksen, Tessa" uniqKey="Fredriksen T" first="Tessa" last="Fredriksen">Tessa Fredriksen</name><affiliation><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></affiliation></author><author><name sortKey="Elie, Nicolas" sort="Elie, Nicolas" uniqKey="Elie N" first="Nicolas" last="Elie">Nicolas Elie</name><affiliation><nlm:affiliation>Imaging Core Facility, CMABIO, Caen University Hospital, Caen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Fauquembergue, Emilie" sort="Fauquembergue, Emilie" uniqKey="Fauquembergue E" first="Emilie" last="Fauquembergue">Emilie Fauquembergue</name><affiliation><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Drouet, Aurelie" sort="Drouet, Aurelie" uniqKey="Drouet A" first="Aurélie" last="Drouet">Aurélie Drouet</name><affiliation><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Leprince, Jerome" sort="Leprince, Jerome" uniqKey="Leprince J" first="Jérôme" last="Leprince">Jérôme Leprince</name><affiliation><nlm:affiliation>Inserm U982, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, France.</nlm:affiliation></affiliation></author><author><name sortKey="Benichou, Jacques" sort="Benichou, Jacques" uniqKey="Benichou J" first="Jacques" last="Benichou">Jacques Benichou</name><affiliation><nlm:affiliation>Biostatistics Unit, Inserm U657, Rouen University Hospital, Rouen University, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Mauillon, Jacques" sort="Mauillon, Jacques" uniqKey="Mauillon J" first="Jacques" last="Mauillon">Jacques Mauillon</name><affiliation><nlm:affiliation>Department of Genetics, Rouen University Hospital, Rouen, France. Department of Gastroenterology, Le Havre Hospital, Le Havre, France.</nlm:affiliation></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><nlm:affiliation>Department of Pathology, Rouen University Hospital, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Sesboue, Richard" sort="Sesboue, Richard" uniqKey="Sesboue R" first="Richard" last="Sesboüé">Richard Sesboüé</name><affiliation><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</nlm:affiliation></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><nlm:affiliation>Department of Digestive Surgery, Rouen University Hospital, Rouen, France.</nlm:affiliation></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><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Pathology, Rouen University Hospital, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Michel, Pierre" sort="Michel, Pierre" uniqKey="Michel P" first="Pierre" last="Michel">Pierre Michel</name><affiliation><nlm:affiliation>Department of Gastroenterology, Rouen University Hospital, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Frebourg, Thierry" sort="Frebourg, Thierry" uniqKey="Frebourg T" first="Thierry" last="Frébourg">Thierry Frébourg</name><affiliation><nlm:affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen, France.</nlm:affiliation></affiliation></author><author><name sortKey="Galon, Jerome" sort="Galon, Jerome" uniqKey="Galon J" first="Jérôme" last="Galon">Jérôme Galon</name><affiliation><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></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><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></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><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26060019</PMID><DateCreated><Year>2015</Year><Month>9</Month><Day>2</Day></DateCreated><DateCompleted><Year>2015</Year><Month>11</Month><Day>25</Day></DateCompleted><DateRevised><Year>2015</Year><Month>9</Month><Day>2</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1538-7445</ISSN><JournalIssue CitedMedium="Internet"><Volume>75</Volume><Issue>17</Issue><PubDate><Year>2015</Year><Month>Sep</Month><Day>1</Day></PubDate></JournalIssue><Title>Cancer research</Title><ISOAbbreviation>Cancer Res.</ISOAbbreviation></Journal><ArticleTitle>Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy.</ArticleTitle><Pagination><MedlinePgn>3446-55</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1158/0008-5472.CAN-14-3051</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>©2015 American Association for Cancer Research.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Maby</LastName><ForeName>Pauline</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tougeron</LastName><ForeName>David</ForeName><Initials>D</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hamieh</LastName><ForeName>Mohamad</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mlecnik</LastName><ForeName>Bernhard</ForeName><Initials>B</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kora</LastName><ForeName>Hafid</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bindea</LastName><ForeName>Gabriela</ForeName><Initials>G</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Angell</LastName><ForeName>Helen K</ForeName><Initials>HK</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fredriksen</LastName><ForeName>Tessa</ForeName><Initials>T</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Elie</LastName><ForeName>Nicolas</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Imaging Core Facility, CMABIO, Caen University Hospital, Caen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fauquembergue</LastName><ForeName>Emilie</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Drouet</LastName><ForeName>Aurélie</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Leprince</LastName><ForeName>Jérôme</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Inserm U982, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Benichou</LastName><ForeName>Jacques</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Biostatistics Unit, Inserm U657, Rouen University Hospital, Rouen University, Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mauillon</LastName><ForeName>Jacques</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Genetics, Rouen University Hospital, Rouen, France. Department of Gastroenterology, Le Havre Hospital, Le Havre, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Le Pessot</LastName><ForeName>Florence</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Department of Pathology, Rouen University Hospital, Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sesboüé</LastName><ForeName>Richard</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tuech</LastName><ForeName>Jean-Jacques</ForeName><Initials>JJ</Initials><AffiliationInfo><Affiliation>Department of Digestive Surgery, Rouen University Hospital, Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sabourin</LastName><ForeName>Jean-Christophe</ForeName><Initials>JC</Initials><AffiliationInfo><Affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Pathology, Rouen University Hospital, Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Michel</LastName><ForeName>Pierre</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Gastroenterology, Rouen University Hospital, Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Frébourg</LastName><ForeName>Thierry</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Galon</LastName><ForeName>Jérôme</ForeName><Initials>J</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Latouche</LastName><ForeName>Jean-Baptiste</ForeName><Initials>JB</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author></AuthorList><Language>ENG</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>Jun</Month><Day>09</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Cancer Res</MedlineTA><NlmUniqueID>2984705R</NlmUniqueID><ISSNLinking>0008-5472</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C418974">FOXP3 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051858">Forkhead Transcription Factors</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000938" MajorTopicYN="N">Antigen-Presenting Cells</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018414" MajorTopicYN="N">CD8-Positive T-Lymphocytes</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015179" MajorTopicYN="N">Colorectal Neoplasms</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003123" MajorTopicYN="N">Colorectal Neoplasms, Hereditary Nonpolyposis</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051858" MajorTopicYN="N">Forkhead Transcription Factors</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016368" MajorTopicYN="N">Frameshift Mutation</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007167" MajorTopicYN="N">Immunotherapy</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016246" MajorTopicYN="N">Lymphocytes, Tumor-Infiltrating</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D053842" MajorTopicYN="Y">Microsatellite Instability</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D057285" MajorTopicYN="N">Precision Medicine</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2014</Year><Month>10</Month><Day>15</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2015</Year><Month>5</Month><Day>14</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2015</Year><Month>6</Month><Day>11</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2015</Year><Month>6</Month><Day>11</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2015</Year><Month>12</Month><Day>15</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">26060019</ArticleId><ArticleId IdType="pii">0008-5472.CAN-14-3051</ArticleId><ArticleId IdType="doi">10.1158/0008-5472.CAN-14-3051</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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