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

• Published in: Clinical cancer research 2020-05, Vol.26 (9), p.2257-2267
• Main Authors: Spassova, Ivelina, Ugurel, Selma, Terheyden, Patrick, Sucker, Antje, Hassel, Jessica C, Ritter, Cathrin, Kubat, Linda, Habermann, Daniel, Farahpour, Farnoush, Saeedghalati, Mohammadkarim, Peiffer, Lukas, Kumar, Rajiv, Schrama, David, Hoffmann, Daniel, Schadendorf, Dirk, Becker, Jürgen C
• Format: Article
• Language: English
• Subjects: Aged; B7-H1 Antigen - antagonists & inhibitors; Bayes Theorem; Biomarkers, Tumor - analysis; Carcinoma, Merkel Cell - drug therapy; Carcinoma, Merkel Cell - immunology; Carcinoma, Merkel Cell - metabolism; Carcinoma, Merkel Cell - pathology; Female; Humans; Immune Checkpoint Inhibitors - therapeutic use; Immunologic Memory; Lymphocytes, Tumor-Infiltrating - immunology; Male; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Receptors, Antigen, T-Cell - genetics; Skin Neoplasms - drug therapy; Skin Neoplasms - immunology; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Treatment Outcome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-2244

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. 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. 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. 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.