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Co-expression patterns of chimeric antigen receptor (CAR)-T cell target antigens in primary and recurrent ovarian
Allyson C Banville1, Maartje C A Wouters2, Ann L Oberg3
1Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Objective:
Chimeric antigen receptor (CAR)-T cell strategies ideally target a surface antigen that is exclusively and uniformly expressed by tumors; however, no such antigen is known for high-grade serous ovarian carcinoma (HGSC). A potential solution involves combinatorial antigen targeting with AND or OR logic-gating. Therefore, we investigated co-expression of CA125, Mesothelin (MSLN) and Folate Receptor alpha (FOLRA) on individual tumor cells in HGSC.
Methods:
RNA expression of CA125, MSLN, and FOLR1 was assessed using TCGA (HGSC) and GTEx (healthy tissues) databases. Antigen expression profiles and CD3+, CD8+ and CD20+ tumor-infiltrating lymphocyte (TIL) patterns were assessed in primary and recurrent HGSC by multiplex immunofluorescence and immunohistochemistry.
Results:
At the transcriptional level, each antigen was overexpressed in >90% of cases; however, MSLN and FOLR1 showed substantial expression in healthy tissues. At the protein level, CA125 was expressed by the highest proportion of cases and tumor cells per case, followed by MSLN and FOLRA. The most promising pairwise combination was CA125 and/or MSLN (OR gate), with 51.9% of cases containing ≥90% of tumor cells expressing one or both antigens. In contrast, only 5.8% of cases contained ≥90% of tumor cells co-expressing CA125 and MSLN (AND gate). Antigen expression patterns showed modest correlations with TIL. Recurrent tumors retained expression of all three antigens and showed increased TIL densities.
Conclusions:
An OR-gated CAR-T cell strategy against CA125 and MSLN would target the majority of tumor cells in most cases. Antigen expression and T-cell infiltration patterns are favorable for this strategy in primary and recurrent disease.
Insights
Chimeric antigen receptor (CAR)-T cell therapy for high-grade serous ovarian carcinoma (HGSC) could target CA125 and Mesothelin (MSLN) using an OR-gate strategy. This approach targets most HGSC tumor cells in primary and recurrent disease.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- High-grade serous ovarian carcinoma (HGSC) lacks a single, tumor-specific surface antigen for effective CAR-T cell targeting.
- Combinatorial antigen targeting with AND or OR logic-gating presents a potential strategy to overcome this limitation.
Purpose of the Study:
- To investigate the co-expression of CA125, Mesothelin (MSLN), and Folate Receptor alpha (FOLRA) on individual HGSC tumor cells.
- To evaluate the feasibility of CAR-T cell strategies targeting these antigens in HGSC.
Main Methods:
- Assessed RNA expression of CA125, MSLN, and FOLR1 using TCGA and GTEx databases.
- Evaluated antigen expression profiles and tumor-infiltrating lymphocyte (TIL) patterns in primary and recurrent HGSC via multiplex immunofluorescence and immunohistochemistry.
Main Results:
- While all three antigens showed high transcriptional expression, MSLN and FOLR1 were also present in healthy tissues.
- At the protein level, CA125 was most prevalent, followed by MSLN and FOLRA.
- An OR-gate combination of CA125 and MSLN targeted ≥90% of tumor cells in 51.9% of cases, whereas an AND-gate strategy was effective in only 5.8% of cases.
- Recurrent tumors maintained antigen expression and showed increased TIL densities.
Conclusions:
- An OR-gated CAR-T cell strategy targeting CA125 and MSLN is a promising approach for HGSC, potentially targeting the majority of tumor cells.
- Favorable antigen expression and T-cell infiltration patterns support this strategy for both primary and recurrent HGSC.
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