Abstract 40P
Background
T cell avidity plays a crucial role in antigen presentation and influences the quality of TCR signaling and T cell metabolic fitness. It is crucial in chronic inflammation e.g. cancer where persistent antigen exposure and chronic T cell stimulation may lead to exhaustion. Thus, mechanistic insights on the roles of CD8+ specificities and T cell avidity of naturally arising tumour-specific T cells where both high (Tethi) and low (Tetlo) avidity T cells recognising the same pMHC co-exist in the same tumour, are crucial for understanding resistance to PD-1 immunotherapy.
Methods
CT26 models were treated with anti-PD-1 on days 3, 6 and 9 following tumour implantation generating variable responses during early tumour development. Tetramer staining and T cell avidity measurement using acoustic force spectroscopy were conducted to determine the frequency and avidity of CD8+ T cells targeting the tumour-specific epitope GSW11. Tethi and Tetlo were functionally characterised using flow cytometry, RNA-seq, in vitro and in vivo cytotoxicity experiments.
Results
Treatment success with anti-PD-1 was associated with the preferential expansion of Tetlo. Tetlo were precursor exhausted with higher expression of Tcf-1 and T-bet, and lower expression of CD39, PD-1 and Eomes compared to Tethi. Pathways related to TCR signaling, cytotoxicity and oxidative phosphorylation were significantly upregulated in Tetlo found in both responding and non-responding tumours compared to Tethi. Interestingly, a small percentage of Tetlo found in the non-responding tumours were functional but metabolically challenged. In vitro studies showed that Tetlo exhibited higher cytotoxicity than Tethi. Curative response was achieved when Tetlo were adoptively transferred and in combination with anti-PD-1.
Conclusions
Targeting subdominant T cell responses with lower avidity against pMHC affinity neoepitopes showed potential for improving PD-1 immunotherapy. Future interventions may consider expanding low avidity populations via adoptive transfer or drugs targeting immunometabolism. These approaches may be combined with non-invasive tumour metabolism imaging and T cell tracking to understand the impact of immunometabolism on T cell dynamics at a system level.
Legal entity responsible for the study
The authors.
Funding
Worldwide Cancer Research Fund (20-0229), Cancer Research UK Programme Grant (A28279).
Disclosure
All authors have declared no conflicts of interest.
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