The tumour immune microenvironment influences neoadjuvant chemoradiotherapy success in esophageal adenocarcinoma (EAC). Complete responders show higher treatment-naïve intratumoral CD8+ T cell levels before treatment than non-complete responders. Understanding mechanisms driving CD8+ T cells exclusion from the TIME is essential to improving outcomes. We performed spatial transcriptomics on treatment-naive CD8-low and high EACs (N = 12). Regions of interest (ROIs) were selected based on tumour annotation by a pathologist. Cancer (CK+) cells and immune (CD45+) cells were analysed within the same ROI. Findings were validated using bulk transcriptome data (TCGA) and metabolic profiling (SCENITH) of fresh tumour specimen (n = 5). Whole transcriptomic profiling showed cancer cell clustering based on T cell infiltration. Cancer cell transcriptomes of CD8-low tumours exhibited reduced antigen presentation and upregulated lipid and mitochondrial metabolism, while CD8-high tumours showed increased cytokine signalling and apoptotic pathways. In CD45+ compartments, CD8-low tumours were enriched for the PGC-1α pathway, linked to mitochondrial biogenesis and immunosuppressive myeloid populations. These findings were supported by TCGA data. SCENITH confirmed mitochondrial dependence of macrophages in CD8-low tumours. Our results suggest that mitochondrial metabolism and impaired antigen presentation contribute to T cell exclusion in EAC. These findings raise the hypothesis that targeting mitochondrial metabolism in these cancers can modulate the anti-tumour immune response and thereby improve the response to chemoradiotherapy.
Cabozantinib, a promising tyrosine kinase inhibitor (TKI), has recently been approved by the Food and Drug Administration (FDA) to treat hepatocellular carcinoma (HCC). However, the objective response rate (ORR) of cabozantinib as monotherapy is low. Therefore, there is an urgent need to develop cabozantinib-based combination therapy. RNA-sequencing was used to analyse the gene expression alterations in HCC cells after cabozantinib treatment. A luciferase reporter assay was used to measure TFEB transcriptional activity. In vitro and in vivo studies were applied to assess the effect of cabozantinib in combination with autophagy inhibitors on HCC. Our results showed that cabozantinib induces autophagic flux, which protects HCC cells from cabozantinib-induced growth inhibition and apoptosis. Further mechanistic studies showed that cabozantinib upregulates Acetyl-CoA Synthetase 2 (ACSS2) and promotes its nuclear translocation, which subsequently activates transcription factor EB (TFEB). TFEB then binds to lysosomal and autophagy gene promoter regions, thereby promoting lysosomal biogenesis and inducing autophagy. In addition, the combination use of an ACSS2 inhibitor or chloroquine (CQ) enhances the antitumor efficacy of cabozantinib in HCC both in vitro and in vivo. Our study proposes a novel molecular mechanism of cabozantinib and provides insights into cabozantinib-based combination therapy for HCC.
The pathogenesis of inflammatory bowel disease (IBD) involves chronic inflammation of the gastrointestinal tract, which predisposes patients to an increased risk of fibrosis and cancer due to prolonged inflammatory stimulation. However, the specific mechanisms underlying secondary gastrointestinal carcinogenesis in individuals with IBD remain poorly elucidated, particularly due to a limited number of studies conducted at single-nuclei level. We investigated the dynamics and interactions of cell subtypes during the progression of IBD-associated cancers through comprehensive analysis including single-nuclei transcriptomics, spatial transcriptomics, ecological dynamic modelling, multiplex immunohistochemistry, in vitro co-culture and in vivo animal studies. The results revealed that CXCL14+ fibroblasts, the primary source of collagen in the microenvironment, play a pivotal role in the inflammation-cancer transition. These fibroblasts progressively increase in abundance during this transition and secreted elevated levels of collagen IV. The increased presence of collagen IV promotes the recruitment and differentiation of SPP1+ macrophages. This interaction ultimately contributes to the development and progression of IBD-associated fibrosis and cancer transformation. Collagen IV, secreted by CXCL14+ fibroblasts, plays a pivotal role in promoting the transition from IBD to cancer. Inhibition of collagen IV secretion not only prevents fibrosis but also hinders the development of inflammation-cancer transition. Our findings are crucial for understanding the mechanisms underlying IBD-associated cancer and developing innovative therapeutic strategies.
In Head and Neck Cancer (HNC), even short delays in treatment can worsen prognosis. We used real-world data to quantify waiting times and identify patient, tumour and health service factors associated with treatment delay in England. Using linked national datasets (Cancer Registry, Cancer Waiting Times, Hospital Episodes Statistics, Radiotherapy and Chemotherapy), we calculated waiting times from referral to first treatment (surgery or (chemo)radiation) and used multivariable logistic regression models to examine factors associated with delay. Of 30,506 patients, 43% experienced treatment delay ( > 62 days from referral). Long delays ( > 90 days) affected 11% of patients treated with primary surgery and 20% of those receiving primary (chemo)radiation. Non-urgent referral (30% of patients) was the strongest predictor of long delay (aOR 4.07, CI: 3.54–4.68). Additional risk-factors included initial assessment at non-specialist (spoke) hospitals, non-oropharyngeal cancers, and higher socio-economic deprivation. Treatment delays in HNC are worsening, particularly for patients treated with primary (chemo)radiation. Referral route is the strongest determinant. Interventions should focus on optimising referral pathways, increasing awareness of HNC symptoms among the public and primary care, and acknowledging the different drivers of delay associated with surgery and (chemo)radiation therapy.
