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 inMCC. These observationswarrant further investigations in larger patient cohorts to confirm their potential value as predictive markers.
| Original language | English |
|---|---|
| Journal | Clinical Cancer Research |
| Volume | 26 |
| Issue number | 9 |
| Pages (from-to) | 2257-2267 |
| Number of pages | 11 |
| ISSN | 1078-0432 |
| DOIs | |
| Publication status | Published - 01.05.2020 |
Funding
S. Ugurel is an employee/paid consultant for Bristol-Myers Squibb, Merck, and Merck Sharp and Dohme. P. Terheyden reports receiving other remuneration from Sanofi, Pfizer, Roche, Bristol-Myers Squibb, Novartis, Roche, and Biofrontera. J.C. Hassel is an employee/paid consultant for Merck Sharp and Dohme, Pierre Fabre, Sanofi, and Sun Pharma, and is an advisory board member/unpaid consultant for Bristol-Myers Squibb and Novartis. J.C. Becker is an employee/paid consultant for Sanofi, Merck Serono, ReProTher, 4SC, Amgen, eTheRNA, and Pfizer, reports receiving commercial research grants from Alcedis, IQVIA, Merck Serono, and Amgen, speakers bureau honoraria from Amgen, Merck Serono, Sanofi, Pfizer, and Recordati, and other remuneration from Incyte. No potential conflicts of interest were disclosed by the other authors. This work was funded by the DKTK site budget OE 0460 EDO3. We thank the patients who participated in this study, their families, and the staff members at the clinical centers who cared for them.
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
