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

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 perfor-mance 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.

Differences in TCR repertoire and T cell activation underlie the divergent outcomes of antitumor immune responses in tumor-eradicating versus tumor-progressing hosts

“…31 62 63 Additionally, clonal expansion may indicate a successful immune response against tumors. 64 Given our finding that T cell activation inversely correlated with tumor volume to a high degree, we anticipated that regressor versus progressor TILs would reside in different clusters, and that progressor TILs would not achieve the same level of clonal expansion as their regressor counterparts. Unexpectedly, we found that T cells in growing tumors demonstrated polyclonal expansion, and that T cells in growing tumors reached each of the different activation states identified on the UMAP.…”

The HDAC Inhibitor Domatinostat Promotes Cell-Cycle Arrest, Induces Apoptosis, and Increases Immunogenicity of Merkel Cell Carcinoma Cells

“…This dramatically changed with the introduction of immunotherapy by immune checkpoint inhibitors, i.e., antibodies blocking programmed cell death protein 1 (PD-1) or programmed cell death protein ligand 1 (PD-L1), which demonstrate remarkable clinical activity (Kaufman et al, 2018;Nghiem et al, 2019). Unfortunately, about half of the patients either show primary or develop secondary resistance to immune checkpoint inhibitors (Spassova et al, 2020). Recent studies demonstrated that one immune evasion mechanism is represented by reduced or lack of major histocompatibility complex (MHC) class I surface expression (Paulson et al, 2014;Paulson et al, 2018;Ritter et al, 2017).…”

High-Throughput Sequencing-Based Analysis of T Cell Repertoire in Lupus Nephritis

“…First of all, the sample size was relatively small, which impaired the statistical power. Considering potential factors that may confound the TCR characteristics, further studies with larger cohorts and long-term outcome measurements in both SLE patients and matched controls are required to better understand the immunological significance of TCR changes (22,23). It would be more enlightening if a large sample enables to identify particular LN-specific TCR sequences.…”