Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers

Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites . However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intr...

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Vydané v:	Nature medicine Ročník 25; číslo 1; s. 89 - 94
Hlavní autori:	Scheper, Wouter, Kelderman, Sander, Fanchi, Lorenzo F, Linnemann, Carsten, Bendle, Gavin, de Rooij, Marije A J, Hirt, Christian, Mezzadra, Riccardo, Slagter, Maarten, Dijkstra, Krijn, Kluin, Roelof J C, Snaebjornsson, Petur, Milne, Katy, Nelson, Brad H, Zijlmans, Henry, Kenter, Gemma, Voest, Emile E, Haanen, John B A G, Schumacher, Ton N
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Nature Publishing Group 01.01.2019
Predmet:	CD8 antigen CD8-Positive T-Lymphocytes - immunology Colorectal cancer Colorectal carcinoma Humans Infiltration Jurkat Cells Lymphocytes Lymphocytes T Lymphocytes, Tumor-Infiltrating - immunology Metastases Neoplasms - immunology Neoplasms - pathology Ovarian cancer Phenotype Receptors, Antigen, T-Cell - metabolism Reproducibility of Results T cell receptors Tumors
ISSN:	1078-8956, 1546-170X, 1546-170X
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Abstract	Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites . However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8 T cells in ovarian and colorectal cancer-two tumor types for which T cell infiltrates form a positive prognostic marker . Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8 T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.
AbstractList	Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites1. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer-two tumor types for which T cell infiltrates form a positive prognostic marker2,3. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites1. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer-two tumor types for which T cell infiltrates form a positive prognostic marker2,3. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire. Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites1. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer—two tumor types for which T cell infiltrates form a positive prognostic marker2,3. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire. Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites . However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8 T cells in ovarian and colorectal cancer-two tumor types for which T cell infiltrates form a positive prognostic marker . Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8 T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.
Author	Haanen, John B A G Hirt, Christian Voest, Emile E Linnemann, Carsten Slagter, Maarten Schumacher, Ton N Snaebjornsson, Petur Kluin, Roelof J C Milne, Katy Nelson, Brad H Dijkstra, Krijn Mezzadra, Riccardo de Rooij, Marije A J Kenter, Gemma Kelderman, Sander Scheper, Wouter Bendle, Gavin Zijlmans, Henry Fanchi, Lorenzo F
Author_xml	– sequence: 1 givenname: Wouter surname: Scheper fullname: Scheper, Wouter organization: Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 2 givenname: Sander surname: Kelderman fullname: Kelderman, Sander organization: Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 3 givenname: Lorenzo F surname: Fanchi fullname: Fanchi, Lorenzo F organization: Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 4 givenname: Carsten surname: Linnemann fullname: Linnemann, Carsten organization: Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 5 givenname: Gavin surname: Bendle fullname: Bendle, Gavin organization: Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 6 givenname: Marije A J surname: de Rooij fullname: de Rooij, Marije A J organization: Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 7 givenname: Christian surname: Hirt fullname: Hirt, Christian organization: Department of Biomedicine, University of Basel, Basel, Switzerland – sequence: 8 givenname: Riccardo surname: Mezzadra fullname: Mezzadra, Riccardo organization: Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 9 givenname: Maarten surname: Slagter fullname: Slagter, Maarten organization: Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 10 givenname: Krijn surname: Dijkstra fullname: Dijkstra, Krijn organization: Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 11 givenname: Roelof J C surname: Kluin fullname: Kluin, Roelof J C organization: Central Genomics Facility, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 12 givenname: Petur orcidid: 0000-0002-1086-8108 surname: Snaebjornsson fullname: Snaebjornsson, Petur organization: Division of Pathology, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 13 givenname: Katy surname: Milne fullname: Milne, Katy organization: Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, British Columbia, Canada – sequence: 14 givenname: Brad H surname: Nelson fullname: Nelson, Brad H organization: Trev and Joyce Deeley Research Centre, BC Cancer, Victoria, British Columbia, Canada – sequence: 15 givenname: Henry surname: Zijlmans fullname: Zijlmans, Henry organization: Department of Gynecologic Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 16 givenname: Gemma surname: Kenter fullname: Kenter, Gemma organization: Department of Gynecologic Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 17 givenname: Emile E surname: Voest fullname: Voest, Emile E organization: Department of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 18 givenname: John B A G orcidid: 0000-0001-5884-7704 surname: Haanen fullname: Haanen, John B A G organization: Department of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 19 givenname: Ton N orcidid: 0000-0003-0517-8804 surname: Schumacher fullname: Schumacher, Ton N email: t.schumacher@nki.nl organization: Division of Molecular Oncology & Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands. t.schumacher@nki.nl
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Snippet	Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T...
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SubjectTerms	CD8 antigen CD8-Positive T-Lymphocytes - immunology Colorectal cancer Colorectal carcinoma Humans Infiltration Jurkat Cells Lymphocytes Lymphocytes T Lymphocytes, Tumor-Infiltrating - immunology Metastases Neoplasms - immunology Neoplasms - pathology Ovarian cancer Phenotype Receptors, Antigen, T-Cell - metabolism Reproducibility of Results T cell receptors Tumors
Title	Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers
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