Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors
T-cell receptor (TCR) redirected T cells are considered as the next generation of care for the treatment of numerous solid tumors. KRAS mutations are driver neoantigens that are expressed in over 25% of all cancers and are thus regarded as ideal targets for Adoptive Cell Therapy (ACT). We have isola...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2021-01-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2021.1936757 |
| _version_ | 1819283925772533760 |
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| author | Pierre Dillard Nicholas Casey Sylvie Pollmann Patrik Vernhoff Gustav Gaudernack Gunnar Kvalheim Sébastien Wälchli Else Marit Inderberg |
| author_facet | Pierre Dillard Nicholas Casey Sylvie Pollmann Patrik Vernhoff Gustav Gaudernack Gunnar Kvalheim Sébastien Wälchli Else Marit Inderberg |
| author_sort | Pierre Dillard |
| collection | DOAJ |
| description | T-cell receptor (TCR) redirected T cells are considered as the next generation of care for the treatment of numerous solid tumors. KRAS mutations are driver neoantigens that are expressed in over 25% of all cancers and are thus regarded as ideal targets for Adoptive Cell Therapy (ACT). We have isolated four KRAS-specific TCRs from a long-term surviving pancreatic cancer patient vaccinated with a mix of mutated KRAS peptides. The sequence of these TCRs could be identified and expressed in primary cells. We demonstrated stable expression of all TCRs as well as target-specific functionality when expressing T cells were co-incubated with target cells presenting KRAS peptides. In addition, these TCRs were all partially co-receptor independent since they were functional in both CD4 and CD8 T cells, thus indicating high affinity. Interestingly, we observed that certain TCRs were able to recognize several KRAS mutations in complex with their cognate Human leukocyte antigen (HLA), suggesting that, here, the point mutations were less important for the HLA binding and TCR recognition, whereas others were single-mutation restricted. Finally, we demonstrated that these peptides were indeed processed and presented, since HLA-matched antigen presenting cells exogenously loaded with KRAS proteins were recognized by TCR-transduced T cells. Taken together, our data demonstrate that KRAS mutations are immunogenic for CD4 T cells and are interesting targets for TCR-based cancer immunotherapy. |
| first_indexed | 2024-12-24T01:39:14Z |
| format | Article |
| id | doaj.art-7fa6611b77e643bf8a6aaec304d6dca2 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-24T01:39:14Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-7fa6611b77e643bf8a6aaec304d6dca22022-12-21T17:22:05ZengTaylor & Francis GroupOncoImmunology2162-402X2021-01-0110110.1080/2162402X.2021.19367571936757Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumorsPierre Dillard0Nicholas Casey1Sylvie Pollmann2Patrik Vernhoff3Gustav Gaudernack4Gunnar Kvalheim5Sébastien Wälchli6Else Marit Inderberg7Oslo University HospitalOslo University HospitalOslo University HospitalOslo University HospitalInstitute for Cancer Research, Oslo University HospitalOslo University HospitalOslo University HospitalOslo University HospitalT-cell receptor (TCR) redirected T cells are considered as the next generation of care for the treatment of numerous solid tumors. KRAS mutations are driver neoantigens that are expressed in over 25% of all cancers and are thus regarded as ideal targets for Adoptive Cell Therapy (ACT). We have isolated four KRAS-specific TCRs from a long-term surviving pancreatic cancer patient vaccinated with a mix of mutated KRAS peptides. The sequence of these TCRs could be identified and expressed in primary cells. We demonstrated stable expression of all TCRs as well as target-specific functionality when expressing T cells were co-incubated with target cells presenting KRAS peptides. In addition, these TCRs were all partially co-receptor independent since they were functional in both CD4 and CD8 T cells, thus indicating high affinity. Interestingly, we observed that certain TCRs were able to recognize several KRAS mutations in complex with their cognate Human leukocyte antigen (HLA), suggesting that, here, the point mutations were less important for the HLA binding and TCR recognition, whereas others were single-mutation restricted. Finally, we demonstrated that these peptides were indeed processed and presented, since HLA-matched antigen presenting cells exogenously loaded with KRAS proteins were recognized by TCR-transduced T cells. Taken together, our data demonstrate that KRAS mutations are immunogenic for CD4 T cells and are interesting targets for TCR-based cancer immunotherapy.http://dx.doi.org/10.1080/2162402X.2021.1936757immunotherapyadoptive cell therapytcrkras |
| spellingShingle | Pierre Dillard Nicholas Casey Sylvie Pollmann Patrik Vernhoff Gustav Gaudernack Gunnar Kvalheim Sébastien Wälchli Else Marit Inderberg Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors OncoImmunology immunotherapy adoptive cell therapy tcr kras |
| title | Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors |
| title_full | Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors |
| title_fullStr | Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors |
| title_full_unstemmed | Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors |
| title_short | Targeting KRAS mutations with HLA class II-restricted TCRs for the treatment of solid tumors |
| title_sort | targeting kras mutations with hla class ii restricted tcrs for the treatment of solid tumors |
| topic | immunotherapy adoptive cell therapy tcr kras |
| url | http://dx.doi.org/10.1080/2162402X.2021.1936757 |
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