Immune checkpoint blockade (ICB) therapies have achieved significant breakthroughs in cancer treatment over the past decade. However, ICB is largely ineffective in desert-type gastric cancer (GC) due to intrinsic tumor heterogeneity and a highly immunosuppressive tumor microenvironment (TME). Transforming tumors from immunosuppressive to immunostimulatory is a potential approach to enhance ICB response. Here, we developed a chromosomal instability (CIN) subtype GC mouse model with an immunoactive TME and a stem cell-originated mouse-derived allograft (MDA) model with an immunosuppressed TME to investigate mechanisms regulating the tumor immunophenotype and uncover therapeutic strategies to remodel the TME. Blocking β-catenin signaling attenuated the immunochemotherapeutic resistance of MDA tumors. The tyrosine kinase inhibitor apatinib reprogrammed the TME by increasing CD8+ T cells and IGHA+ plasma cells infiltration and decreasing M2 macrophages, but apatinib also induced PD-L1 and CD80 expression in both human and mouse desert-type tumors. Oxaliplatin decreased the apatinib-induced expression of immune checkpoints and enhanced the antitumor efficacy of immunotherapy. A prospective clinical trial (NCT04195828) demonstrated that a neoadjuvant regimen of apatinib plus ICB and chemotherapy was effective in patients with desert-type GC. Collectively, these findings identify potential drug targets for immune desert-type GC driven by β-catenin signaling.

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-24-2697DOI Listing

Publication Analysis

Top Keywords

immunosuppressive tumor
8
tumor microenvironment
8
desert-type gastric
8
gastric cancer
8
β-catenin signaling
8
desert-type
5
tme
5
combining apatinib
4
apatinib oxaliplatin
4
oxaliplatin remodels
4

Similar Publications

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a five-year survival rate of just 7%. Its late diagnosis and limited treatment options contribute to poor outcomes. Immunotherapy has had little success due to PDAC's dense and immunosuppressive tumor environment.

View Article and Find Full Text PDF

Blue rubber bleb nevus syndrome: A case report and literature review.

Zhong Nan Da Xue Xue Bao Yi Xue Ban

October 2024

Department of Radiology, Third Xiangya Hospital, Central South University, Changsha 410013, China.

Blue rubber bleb nevus syndrome (BRBNS) is a rare congenital clinical syndrome characterized by venous malformations in multiple organs, including the skin, gastrointestinal tract, liver, and lungs. In June 2022, Third Xiangya Hospital of Central South University admitted a rare case of BRBNS. The patient was hospitalized due to abdominal distension and a history of recurrent hematochezia.

View Article and Find Full Text PDF

Exosome-mediated communication between T cells and dendritic cells: Implications for therapeutic strategies.

Cytokine

March 2025

Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada; CTOAM | Cancer Treatment Options & Management, Vancouver, British Columbia, Canada. Electronic address:

Cell communication is crucial for coordinating physiological functions in multicellular organisms, with exosomes playing a significant role. Exosomes mediate intercellular communication by transporting proteins, lipids, and nucleic acids between cells. These small, membrane-bound vesicles, derived from the endosomal pathway, are integral to various biological processes, including signal transmission and cellular behavior modulation.

View Article and Find Full Text PDF

CAD manipulates tumor intrinsic DHO/UBE4B/NF-κB pathway and fuels macrophage cross-talk, promoting hepatocellular carcinoma metastasis.

Hepatology

March 2025

Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China.

Background And Aims: Portal vein tumor thrombosis (PVTT), an indicator of clinical metastasis, significantly shortens hepatocellular carcinoma (HCC) patients' lifespan, and no effective treatment has been established. We aimed to illustrate mechanisms underlying PVTT formation and tumor metastasis, and identified potential targets for clinical intervention.

Approach And Results: Multi-omics data of 159 HCC patients (including 37 cases with PVTT) was analyzed to identify contributors to PVTT formation and tumor metastasis.

View Article and Find Full Text PDF

Immune suppression sustained allograft acceptance requires PD1 inhibition of CD8+ T cells.

J Immunol

January 2025

Division of Infectious Diseases, Center for Inflammation and Tolerance, Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, United States.

Organ transplant recipients require continual immune-suppressive therapies to sustain allograft acceptance. Although medication nonadherence is a major cause of rejection, the mechanisms responsible for graft loss in this clinically relevant context among individuals with preceding graft acceptance remain uncertain. Here, we demonstrate that skin allograft acceptance in mice maintained with clinically relevant immune-suppressive therapies, tacrolimus and mycophenolate, sensitizes hypofunctional PD1hi graft-specific CD8+ T cells.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!