Single-cell RNA sequencing reveals localized tumourablation and intratumoural immunostimulant deliverypotentiate T cell mediated tumour killing
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Date
2022-06-05Author
Hoover, Ashley R.
Liu, Kaili
DeVette, Christa I.
Krawic, Jason R.
Medcalf, Alexandra D.
West, Connor L.
Hode, Tomas
Lam, Samuel S.K.
Welm, Alana L.
Sun, Xiao-Hong
Hildebrand, William H.
Chen, Wei R.
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Background: Metastatic breast cancer poses great challenge in cancer treatment. N-dihydrogalactochitosan (GC) is a novel immunoadjuvant that stimulates systemic immune responses when administered intratumourally following local tumour ablation. A combination of photothermal therapy (PTT) and GC, referred to as localized ablative immunotherapy (LAIT), extended animal survival and generates an activated B cell phenotype in MMTV-PyMT mouse mammary tumour microenvironment (TME). However, how T cell populations respond to LAIT remains to be elucidated. Methods: Using depletion antibodies, we studied the contributions of CD8+ and CD4+ T cells to the therapeutic effect of LAIT. Using single-cell RNA-sequencing (scRNAseq), we analysed tumour-infiltrating T cell heterogeneity and dissected their transcriptomes upon treatments of PTT, GC, and LAIT (PTT+GC). Results: Loss of CD8+ T cells after LAIT abrogated the therapeutic benefits of LAIT. Ten days after treatment, proportions of CD8+ and CD4+ T cells in untreated TME were 19.2% and 23.0%, respectively. Upon LAIT, both proportions were increased to 25.5% and 36.2%, respectively. In particular, LAIT increased the proportions of naïve and memory cells from a resting state to an activated state. LAIT consistently induced the expression of co-stimulatory molecules, type I IFN responsive genes, and a series of antitumor cytokines, Ifng, Tnf, Il1, and Il17 in CD8+ and CD4+ T cells. LAIT also induced immune checkpoints Pdcd1, Ctla4, and Lag3 expression, consistent with T cell activation. Relevant to clinical translation, LAIT also upregulated genes in CD8+and CD4+T cells that positively correlated with extended survival of breast cancer patients. Conclusions: Overall, our results reveal that LAIT prompts immunological remodelling of T cells by inducing broad proinflammatory responses and inhibiting suppressive signalling to drive antitumour immunity.
DOI
10.1002/ctm2.937Citation
Hoover, AR, Liu, K, DeVette, CI, et al. Single-cell RNA sequencing reveals localized tumour ablation and intratumoural immunostimulant delivery potentiate T cell mediated tumour killing. Clin Transl Med. 2022; 12:e937. https://doi.org/10.1002/ctm2.937
Sponsorship
Financial support was provided by the University of Oklahoma Libraries’ Open Access Fund. National Cancer Institute, Grant/AwardNumbers: R01CA205348, R01CA269897;Oklahoma Center for the Advancement ofScience and Technology, Grant/AwardNumbers: HR16-085, HF20-019.
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