Abstract 1893: The dynamics of T cell clonal repertoire under targeted therapy vs. immunotherapy in melanoma

Abstract

Abstract Introduction. The current standard of care for metastatic melanoma patients utilizes either MAPK pathway inhibitors (MAPKi)-based targeted therapies or immune checkpoint inhibitors (ICI)-based immunotherapies. Almost every melanoma patient treated with MAPKi will relapse in a median of one year, whereas a small subset of ICI-treated melanoma patients experienced prolonged tumor control. Multiple reports have shown that both MAPKi and ICI treatment will induce increased T cell infiltration into the tumor. However, the T-cell receptor (TCR) clonotype dynamics across different therapies (MAPKi vs. ICI) and/or clinical response (responding vs. resistant) is still unknown. This study aims to compare the TCR repertoire dynamics and their associated tumor microenvironment (TME) phenotypes in melanoma pre- vs. post-ICI or MAPKi to see if there are unique patterns associated with better tumor control. Methods. Publicly available bulk RNA-seq data of 345 melanoma samples pre- and post- treatment were downloaded, including two MAPKi (n=116 tumors) and two ICI data sets (n = 229 tumors). All samples were classified into three groups: pre-treatment (PT), on-treatment responding (OT-R), and on-treatment non-responding (OT-NR). T cell clonotype and gene expression were quantified from the RNA-seq data using trust4 and HISAT2/htseq-count, respectively. Although the transcripts of T cells are mixed with tumor cells in the bulk RNA-seq data, the TCR clonotype abundance showed significant correlation with T cell marker expression, offering a measure of robustness in the identification of TCR from bulk tumor derived RNA-seq data. Results. Both MAPKi and ICI therapies significantly increase the TCR count, abundance, diversity, and clonality in OT-R samples compared to PT and OT-NR samples. Intriguingly, we observed significantly higher clonal replacement of PT samples' T cell clonotypes with novel, OT-specific clonotypes under both therapies. Of note, in the tumor subset that responded to the ICI, the increase of these novel TCR were significantly associated with the enrichment of naïve/memory CD4 and CD8 T cell signatures. Conclusions. In melanoma, intratumoral TCR dynamics patterns in response to MAPKi and ICI are mostly similar, except for the upregulation of naïve/memory T cell signatures in the subset of ICI-responder tumors. These insights may eventually lead to better markers for therapy-induced, productive anti-tumor immunity in melanoma. Citation Format: Lizhong Ding, Katie M. Campbell, Egmidio Medina, Kevin Chen, Willy Hugo. The dynamics of T cell clonal repertoire under targeted therapy vs. immunotherapy in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1893.