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.

Katie M Campbell, Maneesha Thaker, Egmidio Medina, Anusha Kalbasi, Arun Singh, Antoni Ribas, Theodore Scott Nowicki

Journal for immunotherapy of cancer 2022 Mar

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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. 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. 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. 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. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Citation

Katie M Campbell, Maneesha Thaker, Egmidio Medina, Anusha Kalbasi, Arun Singh, Antoni Ribas, Theodore Scott Nowicki. 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. 2022 Mar;10(3)