Abstract 4159: Characterization of the T-cell receptor (TCR) repertoire in extensive disease small cell lung cancer (ED SCLC)
Authors: Hussein Maen , Wilks Sharon , Monte Marc , Richards Donald A. , Goldschmidt Jerome H. , Waterhouse David , Wang Lisu , Pant Saumya , Yusko Erik , Emerson Ryan O. , Taverna Darin M. , Desai Kaushal , Mousses Spyro , Qi Zhenhao , Hipp Jason D. , Robins Harlan , Kulig Kimary , Batenchuk Cory 
Published: July 2016

Abstract
Background: The current study explores T-cell (TC) clonality and molecular factors associated with this metric. Tumors employ multiple mechanisms to evade antitumor immune responses. One process involves TC inhibition via upregulation of immune checkpoint (IC) ligands in the tumor microenvironment (TME). Gradual upregulation of inhibitory receptor at their cellular surface results in a decreased capacity to proliferate and activate cytotoxic pathways against tumor cells presenting antigenic peptides.1 In melanoma, this subset of exhausted TCs has been described as highly clonal, where the majority of PD-1-expressing TC population shares the same TCR sequence specific against the same antigenic fragment.2 Previous studies have demonstrated that a clonal TCR repertoire appears to be associated in part with therapeutic responses during IC blockade.3
Methods: We performed TCR sequencing on 82 blood and 73 archival tumor tissue samples collected from ED SCLC patients (pts) in an ongoing longitudinal cohort study in US community oncology practices. Of these, 82 blood and 48 tissue samples had sufficient material available to quantify a clonality metric. To quantify TC abundance as a fraction of total nucleated cells, 82 blood and 58 tissue samples had sufficient material available.
Results: Within the subset of 48 tumor samples, a more clonal (ie, less diverse) TCR repertoire was associated with less necrosis (P≤0.012) and lower levels of inflammatory cell infiltration in the local TME (P≤0.021). When pts were divided into 2 equal groups according to the median clonality level, pts with a less clonal TCR repertoire (n = 24/48) who were treated with non-immune-targeted therapy trended toward a longer overall survival (OS; 446 vs 301 days; P≤0.039). In contrast, the percentage of TCs in the TME did not correlate with improved survival (P≤0.412), necrosis (P≤0.131), and inflammation (P≤0.615). This observation differs from results in melanoma describing the impact of IC blockade where pts responding to therapy were associated with a more clonal TME TC population and increased CD8 TCs in the tumor compartment and at the invasive margin.3 In blood, while a less clonal TCR repertoire was associated with a similar but non-significant trend toward longer survival (P≤0.148), pts with increased TC abundance had longer OS (P≤0.025). No association was observed between clonality in TME and clonality (P≤0.571) or TC abundance (P≤0.965) in blood.
Conclusion: We hypothesize that a diverse TCR repertoire in the TME and increased peripheral TC abundance are 2 predictors of longer OS in ED SCLC. To further explore factors that may influence TC responses in ED SCLC, the current TCR sequencing results will be integrated with transcriptome and whole genome sequencing analyses.
References
1. Wherry EJ. Nat Immunol. 2011;12:492-99.
2. Gros A, et al. J Clin Invest. 2014;124:2246-59.
3. Tumeh PC, et al. Nature. 2014;515:568-71.
Citation Format: Maen Hussein, Sharon Wilks, Marc Monte, Donald A. Richards, Jerome H. Goldschmidt, David Waterhouse, Lisu Wang, Saumya Pant, Erik Yusko, Ryan O. Emerson, Darin M. Taverna, Kaushal Desai, Spyro Mousses, Zhenhao Qi, Jason D. Hipp, Harlan Robins, Kimary Kulig, Cory Batenchuk. Characterization of the T-cell receptor (TCR) repertoire in extensive disease small cell lung cancer (ED SCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4159.