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Updated: Dec 31, 2025
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Predominance of Central Memory T Cells with High T-Cell Receptor Repertoire Diversity is Associated with Response to
Ivelina Spassova1, Selma Ugurel2, Patrick Terheyden3
1Translational Skin Cancer Research, German Consortium for Translational Cancer Research (Deutsches Konsortium für Translationale Krebsforschung; DKTK), Essen, Germany.
Purpose:
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer, which can be effectively controlled by immunotherapy with PD-1/PD-L1 checkpoint inhibitors. However, a significant proportion of patients are characterized by primary therapy resistance. Predictive biomarkers for response to immunotherapy are lacking.
Experimental Design:
We applied Bayesian inference analyses on 41 patients with MCC testing various clinical and biomolecular characteristics to predict treatment response. Further, we performed a comprehensive analysis of tumor tissue-based immunologic parameters including multiplexed immunofluorescence for T-cell activation and differentiation markers, expression of immune-related genes and T-cell receptor (TCR) repertoire analyses in 18 patients, seven objective responders, and 11 nonresponders.
Results:
Bayesian inference analyses demonstrated that among currently discussed biomarkers only unimpaired overall performance status and absence of immunosuppression were associated with response to therapy. However, in responders, a predominance of central memory T cells and expression of genes associated with lymphocyte attraction and activation was evident. In addition, TCR repertoire usage of tumor-infiltrating lymphocytes (TILs) demonstrated low T-cell clonality, but high TCR diversity in responding patients. In nonresponders, terminally differentiated effector T cells with a constrained TCR repertoire prevailed. Sequential analyses of tumor tissue obtained during immunotherapy revealed a more pronounced and diverse clonal expansion of TILs in responders indicating an impaired proliferative capacity among TILs of nonresponders upon checkpoint blockade.
Conclusions:
Our explorative study identified new tumor tissue-based molecular characteristics associated with response to anti-PD-1/PD-L1 therapy in MCC. These observations warrant further investigations in larger patient cohorts to confirm their potential value as predictive markers.
Insights
Predicting Merkel cell carcinoma (MCC) treatment response to immunotherapy is challenging. This study identifies immune cell characteristics and T-cell receptor diversity in tumor tissue as potential predictive biomarkers for anti-PD-1/PD-L1 therapy effectiveness.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Merkel cell carcinoma (MCC) is an aggressive skin cancer.
- Immunotherapy with PD-1/PD-L1 inhibitors is effective but faces primary resistance.
- Predictive biomarkers for immunotherapy response in MCC are needed.
Purpose of the Study:
- To identify predictive biomarkers for anti-PD-1/PD-L1 therapy response in MCC.
- To analyze clinical, biomolecular, and immunological characteristics associated with treatment outcomes.
Main Methods:
- Bayesian inference analysis on 41 MCC patients.
- Multiplexed immunofluorescence for T-cell markers.
- Gene expression analysis and T-cell receptor (TCR) repertoire analysis on tumor tissue.
Main Results:
- Unimpaired performance status and absence of immunosuppression were linked to response.
- Responders showed central memory T cells and genes for lymphocyte activation.
- TCR repertoire analysis revealed high diversity in responders and constrained diversity in non-responders.
- TILs in responders exhibited more pronounced and diverse clonal expansion.
Conclusions:
- New tumor tissue-based molecular characteristics associated with anti-PD-1/PD-L1 therapy response in MCC were identified.
- These findings warrant further investigation in larger cohorts to validate their potential as predictive markers.
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