InVivoPlus anti-mouse PD-1 (CD279)

Reduced chloride channel accessory 4 (CLCA4) levels are linked to cancer development, while its role and mechanism in cancer stem cells (CSCs) remain unclear. In this study, we discovered that decreased CLCA4 expression was evident in CD133+CD44+ colorectal CSCs and chemoresistant colorectal cancer (CRC) cells. Increased expression of CLCA4 inhibited the expression of stemness genes, reduced tumorsphere formation, suppressed the self-renewal, migratory, and invasive capabilities of colorectal CSCs in vitro, and suppressed the tumorigenicity of colorectal CSCs in vivo. Mechanistically, CLCA4 interacted with vimentin, leading to FAK pathway inactivation and subsequent suppression of CSC expansion, while vimentin up-regulation attenuated the effects of CLCA4 down-regulation and established its role in CLCA4-mediated colorectal CSC self-renewal. Decreased CLCA4 expression was positively correlated with colorectal CSC markers and vimentin in clinical specimens. Increased CLCA4 expression promoted the infiltration of cytotoxic CD8+ T cells and enhanced the anti-PD-1 therapeutic efficacy. Our findings suggest that CLCA4 could impede colorectal CSC self-renewal by interacting with vimentin to suppress the FAK signaling pathway, potentially reducing tumor cell stemness and evading immune surveillance. The new findings on cellular and molecular mechanisms underpinning CRC development and progression could offer new perspectives for potential intervention and treatment of CRC.

The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including IL1B high macrophages. Epithelial-proinflammatory niches are prevalent in precursor lesions but become less frequent in LUADs. These niches are conserved in mice and promote alveolar progenitor growth. Targeting inflammation alone or in combination with immune checkpoint blockade in precancerous phase reduces alveolar progenitors. Epithelial-inflammatory niches are stage-specific, shape early LUAD development and represent promising targets for interception.

Background: Tumor-associated macrophages (TAMs) are pivotal mediators of the immunosuppressive tumor immune microenvironment (TIME) in colorectal cancer (CRC). However, genes of TAMs that potentiate immunotherapy remain to be explored. Methods: Single-cell RNA sequencing (scRNA-seq) data were analyzed to identify TAM molecular signatures, which were validated in patient cohorts from Huadong Hospital and TCGA to explore their clinical significance. Multidimensional characterization of CRC TIME and Dipeptidyl peptidase VII (DPP7)-positive TAMs functional state was achieved through cytometry by time-of-flight, multiplex immunofluorescence, in vitro and in vivo experiments. Mechanistic investigations integrating RNA-seq, Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)-based proteomics, and targeted lipid metabolomics have revealed the reprogramming of key metabolic pathways. Finally, the therapeutic potential of DPP7, which targets the enhancement of anti-PD-1 immunotherapy efficacy, was demonstrated. Results: DPP7 was identified as the key gene in TAMs, and DPP7+TAMs correlated with metastasis and worse overall survival in multiple clinical cohorts. Functional characterization demonstrated that DPP7+TAMs drove the immunosuppressive TIME and promoted the exhaustion of CD8+T cells, thus exhibiting M2-polarized features. Mechanistically, DPP7 reduced ubiquitination-induced degradation of Carnitine Palmitoyltransferase 1A (CPT1A) by binding to CPT1A in a mutually exclusive manner with TRIM25, thus enhancing fatty acid oxidation (FAO) in TAMs. This metabolic reprogramming consumes lipids (including triglycerides and free fatty acids), elevates adenosine triphosphate (ATP) generation, and induces an immunosuppressive phenotype. In vivo, DPP7 knockdown in bone marrow-derived macrophages (BMDMs) synergized with anti-PD-1 therapy, achieving significant suppression of subcutaneous xenograft tumor growth and liver metastatic burden by reversing the immunosuppressive TIME. Conclusions: DPP7 is mainly expressed in TAMs and DPP7+TAMs are strongly associated with adverse prognosis in CRC. Mechanistically, DPP7 enhances FAO to promote the M2-polarized phenotype in TAMs, leading to an immunosuppressive TIME. Targeting DPP7+TAMs may potentiate the efficacy of immunotherapy for CRC.

Colorectal cancer (CRC) is a highly immunosuppressive malignancy characterized by limited therapeutic options and a poor prognosis. Within the CRC tumor immune microenvironment (TIME), tumor-associated macrophages (TAMs) represent the predominant immune cell population. This study aimed to characterize the specific macrophage subsets contributing to CRC progression and resistance to immunotherapy.