T-cell stem-like memory cells as a novel biomarker to identify patients with sustained disease control during treatment with PD-(L)1 immunotherapy.

Abstract

2578 Background: Reliable, clinically easily testable biomarkers to monitor the benefit of treatment with immune checkpoint inhibitors (ICI) remain limited. We performed comprehensive analysis of markers defining differentiation and functional status of different populations of peripheral blood T-cell in order to identify biomarkers associates to treatment response in treated patients. Methods: Peripheral blood was analyzed from metastatic patients receiving PD-(L)1–based therapy: anti–PD-(L)1 monotherapy (n=102), combination therapies (n=35), or chemo-immunotherapy (n=14). Sampling time on therapy was heterogeneous, recorded, and included in sensitivity analyses. All patients provided informed consent under IRB approval. A variety of CD4 andCD8 cell populations (naive, stem-like memory [SCM], central memory [CM], effector memory [EM], EMRA/TEMRA). were analyzed using -standardized multiparameter flow cytometry. Pre-specified stem-like–to–effector balance ratios were computed within CD4 and CD8 (SCM/CM and SCM/EM; SCM/EMRA exploratory). Markers analysis included CD45RA, CCR7, CD95, TCF1/TCF7, TOX, TIGIT, and Ki-67). Clinical benefit was assessed by disease control rate (DCR=CR+PR+SD) versus progressive disease ( PD). Biomarkers were analyzed using Mann–Whitney U tests and clustered using unsupervised 1D k-means. Time-to-event analyses used univariable Cox models for time to disease control loss (DCL), defined from ICI initiation to first PD (or discontinuation for progression). Results: Among 151 patients, DCR n=89 and PD n=62, disease control was characterized by a stem-like/early memory blood T-cell profile. DCR showed higher CD4 and CD8 naive and SCM frequencies (p<0.05), whereas PD showed enrichment in differentiated T cell populations including CD4 CM/EM and CD8 EM (p≤0.01 to p<0.0001). Stem-like–to–effector cell ratios were higher in DCR for both CD4 and CD8 (SCM/CM p<0.001; SCM/EM p<0.01) and for CD4 SCM/EMRA (p<0.05). In total CD3 T cells, DCR had higher CD45RA (p<0.001), CCR7 (p<0.05), and TCF1/TCF7 (p<0.05), with lower CD95 (p<0.05) and reduced TIGIT (p<0.01), TOX (p<0.05), and Ki-67 (p<0.05). In Cox models for DCL (inverse-coded; HR>1 favorable), significant associations were observed across subsets, ratio, and marker features (HR range 1.7–4.8; all p<0.05), with the strongest effects for stem-like–to–effector cell ratios and differentiated subset metrics. Associations were observed across PD-(L)1–based regimens. Conclusions: Stem-like memory CD4 and CD8 T cells represent a new marker associated with efficacious response to ICI and DCR while a dominant effector/terminal differentiation profile to DCL and PD. These findings underscore the importance of immune monitoring to identify patients at risk of early loss of treatment benefit and disease progression and to guide treatment modifications.