title: Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy.
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.
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Maby
authors.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.
authors.forename: David
authors.initials: D
authors.lastname: Tougeron
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Hamieh
authors.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.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Mlecnik
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Hafid
authors.initials: H
authors.lastname: Kora
authors.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.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Bindea
authors.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.
authors.forename: Helen K
authors.initials: HK
authors.lastname: Angell
authors.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.
authors.forename: Tessa
authors.initials: T
authors.lastname: Fredriksen
authors.affiliation: Imaging Core Facility, CMABIO, Caen University Hospital, Caen, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Elie
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Fauquembergue
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Drouet
authors.affiliation: Inserm U982, Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leprince
authors.affiliation: Biostatistics Unit, Inserm U657, Rouen University Hospital, Rouen University, Rouen, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Benichou
authors.affiliation: Department of Genetics, Rouen University Hospital, Rouen, France. Department of Gastroenterology, Le Havre Hospital, Le Havre, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Mauillon
authors.affiliation: Department of Pathology, Rouen University Hospital, Rouen, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Le Pessot
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Sesboüé
authors.affiliation: Department of Digestive Surgery, Rouen University Hospital, Rouen, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Tuech
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Pathology, Rouen University Hospital, Rouen, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Sabourin
authors.affiliation: Department of Gastroenterology, Rouen University Hospital, Rouen, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Michel
authors.affiliation: Inserm U1079, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France. Department of Genetics, Rouen University Hospital, Rouen, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Frébourg
authors.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.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Galon
authors.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.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Latouche
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics; D006801:Humans; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008297:Male; D053842:Microsatellite Instability; D057285:Precision Medicine
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors