Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer

Abstract

Chemotherapy prior to immune checkpoint blockade (ICB) treatment appears to improve ICB efficacy but resistance to ICB remains a clinical challenge and is attributed to highly plastic myeloid cells associating with the tumor immune microenvironment (TIME). Here we show by CITE-seq single-cell transcriptomic and trajectory analyses that neoadjuvant low-dose metronomic chemotherapy (MCT) leads to a characteristic co-evolution of divergent myeloid cell subsets in female triple-negative breast cancer (TNBC). Specifically, we identify that the proportion of CXCL16 + myeloid cells increase and a high STAT1 regulon activity distinguishes Programmed Death Ligand 1 (PD-L1) expressing immature myeloid cells. Chemical inhibition of STAT1 signaling in MCT-primed breast cancer sensitizes TNBC to ICB treatment, which underscores the STAT1’s role in modulating TIME. In summary, we leverage single-cell analyses to dissect the cellular dynamics in the tumor microenvironment (TME) following neoadjuvant chemotherapy and provide a pre-clinical rationale for modulating STAT1 in combination with anti-PD-1 for TNBC patients.

The CXCL16-CXCR6 axis in glioblastoma modulates T-cell activity in a spatiotemporal context

“…Indeed, our study showed that CXCR6 + KO T cells are less adherent to tumor-associated myeloid cells and are more functional when directly injected into tumor tissue. This finding is consistent with some emerging data examining the blockade of CXCL16 in breast cancer ( 51 ). In this study, the authors found that blocking CXCL16 prevented CD8 + T-cell infiltration into tumors and decreased PD-1 expression, which was consistent with our observations from our knockout models and adoptive transfer experiments.…”

“…In this study, the authors found that blocking CXCL16 prevented CD8 + T-cell infiltration into tumors and decreased PD-1 expression, which was consistent with our observations from our knockout models and adoptive transfer experiments. This group also demonstrated that the combination of PD1 and CXCL16 blockade led to increases in CD8 + T-cell infiltration in tumors, resulting in the promotion of antitumor immunity ( 51 ). These findings are also consistent with our data showing enhanced antitumor immunity in CXCR6 KO mice treated with anti-PD1 therapy.…”

Histone lactylation bridges metabolic reprogramming and epigenetic rewiring in driving carcinogenesis: Oncometabolite fuels oncogenic transcription

“…Secondary messengers such as cyclic adenosine monophosphate (cAMP) and Ca 2+ play a role in the following signalling events, and their variation depends on the specific alpha subunit type. 80,81 Notably, lactate is capable of signalling through GPR81 and GPR132, both of which are sensitive to protons. 82 GPR81 is detected in different tumours obtained from patients and cancer cell lines.…”

“…Upon the binding of an agonist, the G protein‐coupled receptor (GPCR) alpha subunit undergoes a GDP–GTP exchange. Secondary messengers such as cyclic adenosine monophosphate (cAMP) and Ca 2+ play a role in the following signalling events, and their variation depends on the specific alpha subunit type 80,81 . Notably, lactate is capable of signalling through GPR81 and GPR132, both of which are sensitive to protons 82 …”

Boosting Clear Cell Renal Carcinoma-Specific Drug Discovery Using a Deep Learning Algorithm and Single-Cell Analysis

“…Moreover, fludarabine (F-ara-A; NSC 118218) is a DNA synthesis inhibitor and a fluorinated purine analogue with antitumor activity towards lymphoproliferative malignancies, which can inhibit the activation of STAT1 and STAT1dependent gene transcription induced by cytokines. There have been more than thirty studies of fludarabine over the past few years [61,62]. The docking models in Figure 8C,D demonstrate that these two drugs can target the TF EPAS1.…”