Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells
Identifying tumor-associated T cell epitopes can be laborious. Robbins et al . now report that they used whole-exome sequence data to identify mutated peptides from tumor antigens that are recognized by tumor-infiltrating T cells from patients with melanoma who experienced therapy-associated tumor r...
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| Veröffentlicht in: | Nature medicine 2013-06, Vol.19 (6), p.747-752 |
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| creator | Robbins, Paul F Lu, Yong-Chen El-Gamil, Mona Li, Yong F Gross, Colin Gartner, Jared Lin, Jimmy C Teer, Jamie K Cliften, Paul Tycksen, Eric Samuels, Yardena Rosenberg, Steven A |
| description | Identifying tumor-associated T cell epitopes can be laborious. Robbins
et al
. now report that they used whole-exome sequence data to identify mutated peptides from tumor antigens that are recognized by tumor-infiltrating T cells from patients with melanoma who experienced therapy-associated tumor regressions. The method will contribute to the identification of new tumor-specific epitopes that may further the development of effective T cell therapies for the treatment of patients with melanoma as well as a variety of additional malignancies.
Substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs) in phase 2 clinical trials
1
,
2
. In addition, 40% of patients treated in a recent trial experienced complete regressions of all measurable lesions for at least 5 years following TIL treatment
3
. To evaluate the potential association between the ability of TILs to mediate durable regressions and their ability to recognize potent antigens that presumably include mutated gene products, we developed a new screening approach involving mining whole-exome sequence data to identify mutated proteins expressed in patient tumors. We then synthesized and evaluated candidate mutated T cell epitopes that were identified using a major histocompatibility complex–binding algorithm
4
for recognition by TILs. Using this approach, we identified mutated antigens expressed on autologous tumor cells that were recognized by three bulk TIL lines from three individuals with melanoma that were associated with objective tumor regressions following adoptive transfer. This simplified approach for identifying mutated antigens recognized by T cells avoids the need to generate and laboriously screen cDNA libraries from tumors and may represent a generally applicable method for identifying mutated antigens expressed in a variety of tumor types. |
| doi_str_mv | 10.1038/nm.3161 |
| format | Article |
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et al
. now report that they used whole-exome sequence data to identify mutated peptides from tumor antigens that are recognized by tumor-infiltrating T cells from patients with melanoma who experienced therapy-associated tumor regressions. The method will contribute to the identification of new tumor-specific epitopes that may further the development of effective T cell therapies for the treatment of patients with melanoma as well as a variety of additional malignancies.
Substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs) in phase 2 clinical trials
1
,
2
. In addition, 40% of patients treated in a recent trial experienced complete regressions of all measurable lesions for at least 5 years following TIL treatment
3
. To evaluate the potential association between the ability of TILs to mediate durable regressions and their ability to recognize potent antigens that presumably include mutated gene products, we developed a new screening approach involving mining whole-exome sequence data to identify mutated proteins expressed in patient tumors. We then synthesized and evaluated candidate mutated T cell epitopes that were identified using a major histocompatibility complex–binding algorithm
4
for recognition by TILs. Using this approach, we identified mutated antigens expressed on autologous tumor cells that were recognized by three bulk TIL lines from three individuals with melanoma that were associated with objective tumor regressions following adoptive transfer. This simplified approach for identifying mutated antigens recognized by T cells avoids the need to generate and laboriously screen cDNA libraries from tumors and may represent a generally applicable method for identifying mutated antigens expressed in a variety of tumor types.</description><identifier>ISSN: 1078-8956</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/nm.3161</identifier><identifier>PMID: 23644516</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>692/308/575 ; Adoptive Transfer ; Adult ; Algorithms ; Antigens ; Antigens, Neoplasm - genetics ; Antigens, Neoplasm - immunology ; Biomedicine ; Cancer Research ; DNA sequencing ; Epitopes, T-Lymphocyte ; Exome ; Female ; Gene mutations ; Genetic aspects ; HLA-A Antigens - metabolism ; Humans ; Immune recognition ; Infectious Diseases ; Lesions ; letter ; Lymphocytes ; Lymphocytes, Tumor-Infiltrating - immunology ; Male ; Melanoma ; Melanoma - immunology ; Melanoma - therapy ; Metabolic Diseases ; Methods ; Middle Aged ; Molecular Medicine ; Mutation ; Neurosciences ; Nucleotide sequencing ; Physiological aspects ; Proteins ; T cell receptors ; T cells ; Tumors</subject><ispartof>Nature medicine, 2013-06, Vol.19 (6), p.747-752</ispartof><rights>Springer Nature America, Inc. 2013</rights><rights>COPYRIGHT 2013 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jun 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c700t-7023f461a40a23b379df2597574fada4717778263e125fb0bd16dfb44a6790fc3</citedby><cites>FETCH-LOGICAL-c700t-7023f461a40a23b379df2597574fada4717778263e125fb0bd16dfb44a6790fc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nm.3161$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nm.3161$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23644516$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Robbins, Paul F</creatorcontrib><creatorcontrib>Lu, Yong-Chen</creatorcontrib><creatorcontrib>El-Gamil, Mona</creatorcontrib><creatorcontrib>Li, Yong F</creatorcontrib><creatorcontrib>Gross, Colin</creatorcontrib><creatorcontrib>Gartner, Jared</creatorcontrib><creatorcontrib>Lin, Jimmy C</creatorcontrib><creatorcontrib>Teer, Jamie K</creatorcontrib><creatorcontrib>Cliften, Paul</creatorcontrib><creatorcontrib>Tycksen, Eric</creatorcontrib><creatorcontrib>Samuels, Yardena</creatorcontrib><creatorcontrib>Rosenberg, Steven A</creatorcontrib><title>Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><description>Identifying tumor-associated T cell epitopes can be laborious. Robbins
et al
. now report that they used whole-exome sequence data to identify mutated peptides from tumor antigens that are recognized by tumor-infiltrating T cells from patients with melanoma who experienced therapy-associated tumor regressions. The method will contribute to the identification of new tumor-specific epitopes that may further the development of effective T cell therapies for the treatment of patients with melanoma as well as a variety of additional malignancies.
Substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs) in phase 2 clinical trials
1
,
2
. In addition, 40% of patients treated in a recent trial experienced complete regressions of all measurable lesions for at least 5 years following TIL treatment
3
. To evaluate the potential association between the ability of TILs to mediate durable regressions and their ability to recognize potent antigens that presumably include mutated gene products, we developed a new screening approach involving mining whole-exome sequence data to identify mutated proteins expressed in patient tumors. We then synthesized and evaluated candidate mutated T cell epitopes that were identified using a major histocompatibility complex–binding algorithm
4
for recognition by TILs. Using this approach, we identified mutated antigens expressed on autologous tumor cells that were recognized by three bulk TIL lines from three individuals with melanoma that were associated with objective tumor regressions following adoptive transfer. This simplified approach for identifying mutated antigens recognized by T cells avoids the need to generate and laboriously screen cDNA libraries from tumors and may represent a generally applicable method for identifying mutated antigens expressed in a variety of tumor types.</description><subject>692/308/575</subject><subject>Adoptive Transfer</subject><subject>Adult</subject><subject>Algorithms</subject><subject>Antigens</subject><subject>Antigens, Neoplasm - genetics</subject><subject>Antigens, Neoplasm - immunology</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>DNA sequencing</subject><subject>Epitopes, T-Lymphocyte</subject><subject>Exome</subject><subject>Female</subject><subject>Gene mutations</subject><subject>Genetic aspects</subject><subject>HLA-A Antigens - metabolism</subject><subject>Humans</subject><subject>Immune recognition</subject><subject>Infectious Diseases</subject><subject>Lesions</subject><subject>letter</subject><subject>Lymphocytes</subject><subject>Lymphocytes, Tumor-Infiltrating - immunology</subject><subject>Male</subject><subject>Melanoma</subject><subject>Melanoma - immunology</subject><subject>Melanoma - therapy</subject><subject>Metabolic Diseases</subject><subject>Methods</subject><subject>Middle Aged</subject><subject>Molecular Medicine</subject><subject>Mutation</subject><subject>Neurosciences</subject><subject>Nucleotide sequencing</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>T cell receptors</subject><subject>T 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exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells</title><author>Robbins, Paul F ; Lu, Yong-Chen ; El-Gamil, Mona ; Li, Yong F ; Gross, Colin ; Gartner, Jared ; Lin, Jimmy C ; Teer, Jamie K ; Cliften, Paul ; Tycksen, Eric ; Samuels, Yardena ; Rosenberg, Steven A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c700t-7023f461a40a23b379df2597574fada4717778263e125fb0bd16dfb44a6790fc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>692/308/575</topic><topic>Adoptive Transfer</topic><topic>Adult</topic><topic>Algorithms</topic><topic>Antigens</topic><topic>Antigens, Neoplasm - genetics</topic><topic>Antigens, Neoplasm - immunology</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>DNA sequencing</topic><topic>Epitopes, T-Lymphocyte</topic><topic>Exome</topic><topic>Female</topic><topic>Gene 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medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Robbins, Paul F</au><au>Lu, Yong-Chen</au><au>El-Gamil, Mona</au><au>Li, Yong F</au><au>Gross, Colin</au><au>Gartner, Jared</au><au>Lin, Jimmy C</au><au>Teer, Jamie K</au><au>Cliften, Paul</au><au>Tycksen, Eric</au><au>Samuels, Yardena</au><au>Rosenberg, Steven A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells</atitle><jtitle>Nature medicine</jtitle><stitle>Nat Med</stitle><addtitle>Nat Med</addtitle><date>2013-06-01</date><risdate>2013</risdate><volume>19</volume><issue>6</issue><spage>747</spage><epage>752</epage><pages>747-752</pages><issn>1078-8956</issn><eissn>1546-170X</eissn><abstract>Identifying tumor-associated T cell epitopes can be laborious. Robbins
et al
. now report that they used whole-exome sequence data to identify mutated peptides from tumor antigens that are recognized by tumor-infiltrating T cells from patients with melanoma who experienced therapy-associated tumor regressions. The method will contribute to the identification of new tumor-specific epitopes that may further the development of effective T cell therapies for the treatment of patients with melanoma as well as a variety of additional malignancies.
Substantial regressions of metastatic lesions have been observed in up to 70% of patients with melanoma who received adoptively transferred autologous tumor-infiltrating lymphocytes (TILs) in phase 2 clinical trials
1
,
2
. In addition, 40% of patients treated in a recent trial experienced complete regressions of all measurable lesions for at least 5 years following TIL treatment
3
. To evaluate the potential association between the ability of TILs to mediate durable regressions and their ability to recognize potent antigens that presumably include mutated gene products, we developed a new screening approach involving mining whole-exome sequence data to identify mutated proteins expressed in patient tumors. We then synthesized and evaluated candidate mutated T cell epitopes that were identified using a major histocompatibility complex–binding algorithm
4
for recognition by TILs. Using this approach, we identified mutated antigens expressed on autologous tumor cells that were recognized by three bulk TIL lines from three individuals with melanoma that were associated with objective tumor regressions following adoptive transfer. This simplified approach for identifying mutated antigens recognized by T cells avoids the need to generate and laboriously screen cDNA libraries from tumors and may represent a generally applicable method for identifying mutated antigens expressed in a variety of tumor types.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>23644516</pmid><doi>10.1038/nm.3161</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Nature medicine, 2013-06, Vol.19 (6), p.747-752 |
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| source | MEDLINE; SpringerLink_现刊; Nature |
| subjects | 692/308/575 Adoptive Transfer Adult Algorithms Antigens Antigens, Neoplasm - genetics Antigens, Neoplasm - immunology Biomedicine Cancer Research DNA sequencing Epitopes, T-Lymphocyte Exome Female Gene mutations Genetic aspects HLA-A Antigens - metabolism Humans Immune recognition Infectious Diseases Lesions letter Lymphocytes Lymphocytes, Tumor-Infiltrating - immunology Male Melanoma Melanoma - immunology Melanoma - therapy Metabolic Diseases Methods Middle Aged Molecular Medicine Mutation Neurosciences Nucleotide sequencing Physiological aspects Proteins T cell receptors T cells Tumors |
| title | Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells |
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