Open AccessSingle‐cell RNA sequencing reveals localized tumour ablation and intratumoural immunostimulant delivery potentiate T cell mediated tumour killing
Author(s) -
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 XiaoHong,
Hildebrand William H.,
Chen Wei R.
Publication year - 2022
Publication title -
clinical and translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
H-Index - 1
ISSN - 2001-1326
DOI - 10.1002/ctm2.937
Subject(s) - cd8 , cancer research , immune system , tumor microenvironment , immunotherapy , t cell , cytotoxic t cell , biology , immunology , medicine , microbiology and biotechnology , in vitro , biochemistry
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.