A-S.B.76: Effects of Checkpoint Inhibitor Therapy on Immune Cell Composition in Primary Tumor Sites and Metastases
A tumor’s response to therapy is driven by a complex interplay of tumor-intrinsic and -extrinsic factors, with the tumor microenvironment (TME) serving as a critical extrinsic determinant. The TME is highly complex and dynamic, significantly influencing disease progression by contributing to both anti-tumor immunity and tumor-promoting immunosuppression, primarily through its diverse immune cell components. Immunotherapies, particularly immune checkpoint inhibitors (ICIs), enhance anti-tumor functions, largely by restoring exhausted T cell activation and overcoming immune evasion. However, response to these therapies remains limited and exhibits large heterogeneity among patients, highlighting the need to better understand the underlying mechanisms driving therapeutic efficacy and resistance.
To address this need, we conducted a comprehensive transcriptomic analysis integrating bulk RNA sequencing (n=6,103) and single-cell RNA sequencing (n=415) datasets of patients with solid tumors treated with ICI therapy for which we have extensive clinical information. This approach enabled us to characterize the TME landscape across large clinical cohorts. We identified specific relative immune cell compositions present in TME prior to therapy that serve as predictors of therapy outcome. Furthermore, we mapped the compositional changes within the TME induced by ICI treatment. Specifically, our investigation focused on the distinct roles of lymphocyte subpopulations and their complex cellular interactions within the TME, providing novel insights into the mechanistic drivers of ICI response. These results reveal informative biomarkers linked to the TME and highlight potential new therapeutic targets to improve patient outcomes.
Co-authors: Said Aktas, Samuel Rutz, Adrian Weich, Celine Marban-Doran, Cary M Looney, Timothy Hickling, Bruno Gomes, Sai Reddy, Jehad Charo, Lena Voith von Voithenberg
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