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

doi:10.1136/jitc-2021-004190

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

J Immunother Cancer. 2022 Mar;10(3):e004190. doi: 10.1136/jitc-2021-004190.

Authors

Katie M Campbell¹, Maneesha Thaker^{1

2}, Egmidio Medina¹, Anusha Kalbasi^{3

4}, Arun Singh¹, Antoni Ribas^{1

2

4

5

6}, Theodore Scott Nowicki^{7

8

9

10}

Affiliations

¹ Medicine, Division of Hematology/Oncology, University of California Los Angeles, Los Angeles, California, USA.
² Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.
³ Radiation Oncology, University of California, Los Angeles, Los Angeles, California, USA.
⁴ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA.
⁵ Surgery, Division of Surgical Oncology, University of California, Los Angeles, Los Angeles, California, USA.
⁶ Parker Institute for Cancer Immunotherapy, San Francisco, California, USA.
⁷ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA tnowicki@mednet.ucla.edu.
⁸ Pediatrics, Division of Pediatric Hematology/Oncology, University of California, Los Angeles, Los Angeles, California, USA.
⁹ Microbiology, Immunology, & Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA.
¹⁰ Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California, USA.

Abstract

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.

Keywords: adoptive; immune evation; immunotherapy; sarcoma; tumor escape; tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Neoplasm
Cell- and Tissue-Based Therapy
Humans
Sarcoma, Synovial* / genetics
Sarcoma, Synovial* / therapy
T-Lymphocytes
Wnt Signaling Pathway

Substances

Antigens, Neoplasm

Abstract

Publication types

MeSH terms

Substances

Grants and funding