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Predominance of Central Memory T Cells with High T-Cell Receptor Repertoire Diversity is Associated with Response to PD-1/PD-L1 Inhibition in Merkel Cell Carcinoma
- Source :
- Clinical Cancer Research. 26:2257-2267
- Publication Year :
- 2020
- Publisher :
- American Association for Cancer Research (AACR), 2020.
-
Abstract
- 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.
- Subjects :
- Male
0301 basic medicine
Cancer Research
Skin Neoplasms
medicine.medical_treatment
Lymphocyte
Programmed Cell Death 1 Receptor
Receptors, Antigen, T-Cell
Medizin
B7-H1 Antigen
03 medical and health sciences
Lymphocytes, Tumor-Infiltrating
0302 clinical medicine
Antigen
PD-L1
Biomarkers, Tumor
medicine
Carcinoma
Humans
Immune Checkpoint Inhibitors
Aged
biology
Merkel cell carcinoma
business.industry
T-cell receptor
Bayes Theorem
Immunotherapy
medicine.disease
Carcinoma, Merkel Cell
Treatment Outcome
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Cancer research
biology.protein
Female
Skin cancer
business
Immunologic Memory
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 26
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....118a544457d321110f4b5e3b150a5b97