e007870.full.pdf (3.75 MB)
Quantifying the impact of immunotherapy on RNA dynamics in cancer.
journal contributionposted on 2023-11-06, 11:17 authored by Ieva Usaite, Dhruva Biswas, Krijn Dijkstra, Thomas BK Watkins, Oriol Pich, Clare Puttick, Mihaela Angelova, Krupa Thakkar, Crispin Hiley, Nicolai Birkbak, Marleen Kok, Simone Zaccaria, Yin Wu, Kevin Litchfield, Charles Swanton, Nnennaya Kanu
BACKGROUND: Checkpoint inhibitor (CPI) immunotherapies have provided durable clinical responses across a range of solid tumor types for some patients with cancer. Nonetheless, response rates to CPI vary greatly between cancer types. Resolving intratumor transcriptomic changes induced by CPI may improve our understanding of the mechanisms of sensitivity and resistance. METHODS: We assembled a cohort of longitudinal pre-therapy and on-therapy samples from 174 patients treated with CPI across six cancer types by leveraging transcriptomic sequencing data from five studies. RESULTS: Meta-analyses of published RNA markers revealed an on-therapy pattern of immune reinvigoration in patients with breast cancer, which was not discernible pre-therapy, providing biological insight into the impact of CPI on the breast cancer immune microenvironment. We identified 98 breast cancer-specific correlates of CPI response, including 13 genes which are known IO targets, such as toll-like receptors TLR1, TLR4, and TLR8, that could hold potential as combination targets for patients with breast cancer receiving CPI treatment. Furthermore, we demonstrate that a subset of response genes identified in breast cancer are already highly expressed pre-therapy in melanoma, and additionally we establish divergent RNA dynamics between breast cancer and melanoma following CPI treatment, which may suggest distinct immune microenvironments between the two cancer types. CONCLUSIONS: Overall, delineating longitudinal RNA dynamics following CPI therapy sheds light on the mechanisms underlying diverging response trajectories, and identifies putative targets for combination therapy.