Spatial profiling reveals association between WNT pathway activation and T-cell exclusion in acquired resistance of synovial sarcoma to NY-ESO-1 transgenic T-cell therapy
Background Genetically engineered T-cell immunotherapies for adoptive cell transfer (ACT) have emerged as a promising form of cancer treatment, but many of these patients develop recurrent disease. Furthermore, delineating mechanisms of resistance may be challenging since the analysis of bulk tumor...
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| Language: | English |
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004190.full |
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| author | Arun Singh Antoni Ribas Theodore Scott Nowicki Katie M Campbell Anusha Kalbasi Maneesha Thaker Egmidio Medina |
| author_facet | Arun Singh Antoni Ribas Theodore Scott Nowicki Katie M Campbell Anusha Kalbasi Maneesha Thaker Egmidio Medina |
| author_sort | Arun Singh |
| collection | DOAJ |
| description | Background Genetically engineered T-cell immunotherapies for adoptive cell transfer (ACT) have emerged as a promising form of cancer treatment, but many of these patients develop recurrent disease. Furthermore, delineating mechanisms of resistance may be challenging since the analysis of bulk tumor profiling can be complicated by spatial heterogeneity.Methods Tumor samples were collected from a patient with synovial sarcoma who developed acquired resistance to ACT targeting NY-ESO-1. Biopsies (primary, progressive metastasis, and recurrence) were subjected to bulk tumor DNA and RNA sequencing, as well as high-dimensional spatial profiling of RNA and protein targets. Untreated and progressive lesions were compared with identified patterns associated with acquired resistance to ACT.Results Gene expression patterns due to immune activity and infiltration were diluted in bulk tumor sequencing. The metastasis was enriched for tumor regions with increased CTNNB1 (encoding beta-catenin), which were negatively associated with the expression of T-cell surface proteins and antigen presentation machinery. Spatial profiling was most highly concordant with bulk sequencing in the lesions with decreased spatial heterogeneity.Conclusions Complementary use of bulk and spatial profiling enables more accurate interrogation of tumor specimens, particularly to address complex questions regarding immunotherapeutic mechanisms. Our study uses this approach to demonstrate a mechanism of T-cell exclusion and resistance to cellular immunotherapy in synovial sarcoma. |
| format | Article |
| id | doaj-art-ea334eb5ab02432e909f5ff78f775eb8 |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ea334eb5ab02432e909f5ff78f775eb82025-08-20T03:05:20ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-004190Spatial profiling reveals association between WNT pathway activation and T-cell exclusion in acquired resistance of synovial sarcoma to NY-ESO-1 transgenic T-cell therapyArun Singh0Antoni Ribas1Theodore Scott Nowicki2Katie M Campbell3Anusha Kalbasi4Maneesha Thaker5Egmidio Medina61 Department of Ophthalmic Oncology, Cleveland Clinic Cole Eye Institute, Cleveland, Ohio, USA4University of California Los Angeles, Los Angeles, CA, USA4 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA1 Medicine, Division of Hematology/Oncology, University of California Los Angeles, Los Angeles, California, USA4Stanford Medicine, Stanford, CA, USA1 Medicine, Division of Hematology/Oncology, University of California Los Angeles, Los Angeles, California, USA1 Medicine, Division of Hematology/Oncology, University of California Los Angeles, Los Angeles, California, USABackground Genetically engineered T-cell immunotherapies for adoptive cell transfer (ACT) have emerged as a promising form of cancer treatment, but many of these patients develop recurrent disease. Furthermore, delineating mechanisms of resistance may be challenging since the analysis of bulk tumor profiling can be complicated by spatial heterogeneity.Methods Tumor samples were collected from a patient with synovial sarcoma who developed acquired resistance to ACT targeting NY-ESO-1. Biopsies (primary, progressive metastasis, and recurrence) were subjected to bulk tumor DNA and RNA sequencing, as well as high-dimensional spatial profiling of RNA and protein targets. Untreated and progressive lesions were compared with identified patterns associated with acquired resistance to ACT.Results Gene expression patterns due to immune activity and infiltration were diluted in bulk tumor sequencing. The metastasis was enriched for tumor regions with increased CTNNB1 (encoding beta-catenin), which were negatively associated with the expression of T-cell surface proteins and antigen presentation machinery. Spatial profiling was most highly concordant with bulk sequencing in the lesions with decreased spatial heterogeneity.Conclusions Complementary use of bulk and spatial profiling enables more accurate interrogation of tumor specimens, particularly to address complex questions regarding immunotherapeutic mechanisms. Our study uses this approach to demonstrate a mechanism of T-cell exclusion and resistance to cellular immunotherapy in synovial sarcoma.https://jitc.bmj.com/content/10/3/e004190.full |
| spellingShingle | Arun Singh Antoni Ribas Theodore Scott Nowicki Katie M Campbell Anusha Kalbasi Maneesha Thaker Egmidio Medina Spatial profiling reveals association between WNT pathway activation and T-cell exclusion in acquired resistance of synovial sarcoma to NY-ESO-1 transgenic T-cell therapy Journal for ImmunoTherapy of Cancer |
| title | Spatial profiling reveals association between WNT pathway activation and T-cell exclusion in acquired resistance of synovial sarcoma to NY-ESO-1 transgenic T-cell therapy |
| title_full | Spatial profiling reveals association between WNT pathway activation and T-cell exclusion in acquired resistance of synovial sarcoma to NY-ESO-1 transgenic T-cell therapy |
| title_fullStr | Spatial profiling reveals association between WNT pathway activation and T-cell exclusion in acquired resistance of synovial sarcoma to NY-ESO-1 transgenic T-cell therapy |
| title_full_unstemmed | Spatial profiling reveals association between WNT pathway activation and T-cell exclusion in acquired resistance of synovial sarcoma to NY-ESO-1 transgenic T-cell therapy |
| title_short | Spatial profiling reveals association between WNT pathway activation and T-cell exclusion in acquired resistance of synovial sarcoma to NY-ESO-1 transgenic T-cell therapy |
| title_sort | spatial profiling reveals association between wnt pathway activation and t cell exclusion in acquired resistance of synovial sarcoma to ny eso 1 transgenic t cell therapy |
| url | https://jitc.bmj.com/content/10/3/e004190.full |
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