Abstract 1240: Peripherally measured T cell self-renewal capacity associates with response to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC)
Authors: Maniar Rohan , Wang Peter H. , Washburn Robert S. , Rizvi Naiyer A. , Reiner Steven L. , Henick Brian S. 
Published: June 2022

Recent studies have suggested that ICB does not primarily restore function to terminally exhausted T cells, but instead drives proliferation and differentiation of progenitor T cells into fresh effector cells. T cell factor 1 (TCF1) marks and maintains T cell self-renewal while repressing differentiation and has been associated with increased antitumor activity. These findings suggest ICB may depend on the continued availability of self-renewing TCF1+ progenitor T cells as the source of fresh effector cells. We hypothesized that characterizing the immunophenotype of T cells in the peripheral blood, with a focus on markers of self-renewal, might be predictive of ICB response. Utilizing an institution-wide biospecimen repository, we evaluated peripheral blood samples using multi-parametric flow cytometry from patients with metastatic NSCLC treated with single-agent ICB who experienced durable clinical benefit (DCB; &gt;1 year of treatment and/or clinical response &gt;1 year) or primary resistance (RES; &lt;6 months of treatment with evidence of disease progression). Our analysis focused on a CCR7- T cell subset, which is characterized by lower proportions of TCF1+ cells but increase during active immune responses. We analyzed samples collected from a cohort of 22 patients, 11 of whom had DCB and 11 with RES. In the pre-treatment samples (n=22), we determined that the frequency of TCF1+CCR7- CD8+ T cells was significantly higher in patients with DCB compared to patients with RES (32.6% v. 19.0%; P = 0.0452). Importantly, the median progression free survival was 17.0 months in patients with TCF1+ frequency above the median compared to 3.0 months in patients with TCF1+ frequency below the median (HR 0.43; P = 0.0185). Among the on-treatment samples (n=19), there was an increased frequency of PD1+ expression within the CCR7- CD8+ T cell subset compared to the paired baseline samples. Examination of those therapy-expanded PD1+ T cells revealed differences in the composition of TCF1+ versus TCF1- fractions in relation to treatment outcome. The mean ratio of TCF1+ to TCF1- amongst PD1+CCR7- T cells on-treatment was found to be significantly higher in the DCB group (1.483 [DCB] v. 0.4791 [RES], P=&lt;0.0001). In this analysis, we identified a pattern of pre-and on-treatment T cell populations that correlates with durable benefit from ICB in patients with NSCLC. We observed that the frequency of TCF1 expression in the more differentiated effector memory T cell subsets prior to treatment correlates with DCB. While on treatment, both groups experienced expansion of PD1+ CD8 T cells, but the presence of greater fractions of TCF1+ T cells in the PD1+ CD8 T cell population correlates with DCB. This finding suggests that persistence and mobilization of self-renewing progenitor T cells is associated with long-lived ICB-induced anti-tumor activity.

Citation Format: Rohan Maniar, Peter H. Wang, Robert S. Washburn, Naiyer A. Rizvi, Steven L. Reiner, Brian S. Henick. Peripherally measured T cell self-renewal capacity associates with response to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1240.