Colon Liver PD-L1

Cancer immunotherapy based on bioengineering of bacteria can effectively increase anticancer immune responses. However, few studies have investigated the antitumor potential of engineering Proteus mirabilis . Here, we genetically engineered P. mirabilis to overexpress Vibrio vulnificus flagellin B (FlaB) protein in a murine CT26 tumor model. We found that a large number of FlaB-expressing P. mirabilis colonized tumor tissues, enhanced T cell infiltration and secretion of cytokines and cytotoxic proteins in tumors, and significantly restrained tumor growth...

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment...

BACKGROUND: Intra-abdominal desmoplastic small round cell tumor (IDSRCT) is a rare entity (0.2-0.74 cases per million people per year), which predominantly occurs in young men. It may present as an abdominal mass with pain, distention, and constipation. IDSRCT has a very poor prognosis, with 5-year overall survival estimated at 15%-30%. Diagnosis is made with tissue biopsy. CASE DESCRIPTION: We present a case of a 28-year-old man with a history of schizophrenia and depression who presented to an emergency room (ER) in November 2022 with constipation and pelvic pain...

BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastasis is reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Here, we aimed to investigate the role of IL-10 in liver metastasis formation and decipher its therapeutic potential in affecting immunotherapy effectiveness. METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively...

A 56-year-old man referred to our hospital for cecum cancer. Enhanced computed tomography (CT) found swollen reginal lymph nodes and liver metastasis. Magnetic Resonance Imaging (MRI) revealed a solitary lesion on liver (S2). We performed a laparoscopic ileocolic resection and liver partial resection. Tumor pathology showed that these tumors were moderate-differentiated adenocarcinoma (pT3N2bM1 Stage IVA). Genetic examination revealed MSI-high, KRAS wild type, and BRAF wild type. After surgery, two liver metastases were found in S4 and S7 as new lesion in EOB-MRI...

BACKGROUND: The most common site of metastasis in colorectal cancer (CRC) is the liver and liver metastases occur in more than 50% of patients during diagnosis or treatment. The occurrence of metastasis depends on a series of events known as the invasive-metastasis cascade. Currently, the underlying genes and pathways regulating metastasis initiation in the liver microenvironment are unknown. METHODS: We performed systematic CRISPR/Cas9 screening using an in vivo mouse model of CRC liver metastasis to identify key regulators of CRC metastasis...

Metastasis of colorectal cancer (CRC) is a leading cause of mortality among CRC patients. Elevated COX-2 and PD-L1 expression in colon cancer tissue has been linked to distant metastasis of tumor cells. Although COX-2 inhibitors and immune checkpoint inhibitors demonstrate improved anti-tumor efficacy, their toxicity and variable therapeutic effects in individual patients raise concerns. To address this challenge, it is vital to identify traditional Chinese medicine components that modulate COX-2 and PD-1/PD-L1: rosmarinic acid (RA) exerts striking inhibitory effect on COX-2, while ginsenoside Rg1 (GR) possesses the potential to suppress the binding of PD-1/PD-L1...

Microsatellite-stable colorectal cancer (MSS-CRC) is highly refractory to immunotherapy. Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve MSS-CRC patient outcomes. Here, we demonstrate that high tumor expression of the core autophagy gene ATG16L1 is associated with poor clinical response to anti-PD-L1 therapy in KRAS-mutant tumors from IMblaze370 (NCT02788279), a large phase III clinical trial of atezolizumab (anti-PD-L1) in advanced metastatic MSS-CRC. Deletion of Atg16l1 in engineered murine colon cancer organoids inhibits tumor growth in primary (colon) and metastatic (liver and lung) niches in syngeneic female hosts, primarily due to increased sensitivity to IFN-γ-mediated immune pressure...

OBJECTIVE: In this study, we investigated the relationship between programmed cell death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) expression in colon adenocarcinoma tumor budding. METHODS: This study included 122 patients with colon adenocarcinomas. The largest sample of formaldehyde-fixed paraffin-embedded tumor tissues was selected for analysis. Expression of membranous PD-L1 (clone 22C3) and the Combined Positive Score (CPS) in tumor tissues was calculated and graded according to the percentages of peritumoral and intratumoral tumor cells (0 %, 1 %, 1-5 %, >5 %)...

Thymic carcinoma (TC) is a rare and aggressive malignancy of the thymus associated with less than 25% 5 years survivability. Our case report showcases the successful treatment of advanced metastatic TC using a multidisciplinary approach and the utility of checkpoint inhibitors in treatment of recurrent TC. A 50-year-old man presented with Raynaud's phenomenon and was found to have a stage IVb TC (T3N2M0). Eight months after management with neoadjuvant chemotherapy, surgical resection and adjuvant chemoradiotherapy, patient was diagnosed with metastasis of TC to the liver and a concurrent stage III (T2N1M0) primary sigmoid colon adenocarcinoma...

Checkpoint inhibitors are monoclonal antibodies that elicit an anti-tumor response by stimulating immune system. Their use has improved the treatment of different types of cancer such as melanoma, breast carcinoma, lung, stomach, colon, liver, renal cell carcinoma, and Hodgkin's lymphoma, but several adverse events have been reported. Although the etiology of these effects is not completely understood, an uncontrolled activation of the immune system has been postulated. Indeed, some studies showed a cross reactivity of T cells, which acted against tumor antigens as well as antigens in the tissues of patients who developed immune-related adverse events...

Programmed cell death receptor 1 (PD-1) and its ligand PD-L1 are particularly interesting immune checkpoint proteins for human cancer treatment. Positron emission tomography (PET) imaging allows for the dynamic monitoring of PD-L1 status during tumor progression, thus informing patients' response index. Herein, we report the synthesis of two linear peptide-based radiotracers, [64 Cu]/[68 Ga]HKP2201 and [64 Cu]/[68 Ga]HKP2202, and validate their utility for PD-L1 visualization in preclinical models. The precursor peptide HKP2201 was derived from a linear peptide ligand, CLP002, which was previously identified by phage display and showed nanomolar affinity toward PD-L1...

This study aimed to establish the radio-immune imaging protocol on the basis of Avidin/Biotin system. The programmed death-ligand 1 (PD-L1) antibody (Atezolizumab) was employed as the primary molecule in targeting PD-L1, and the two-step strategy, consisting of the first injection of Avidin-conjugated PD-L1 monoclonal antibody (Atezolizumab) and the second injection of 7.4 MBq 68 Ga-Biotin with a 60 h interval, was then verified on the colon cancer-bearing mice. PET imaging was performed at 30, 90, 180 min to measure the standard uptake value and tumor to liver ratios...

PURPOSE: Our study was to investigate the correlation correlation between FDG uptake and PD-L1 expression of liver metastasis in patients with colon cancer, and to determine the value of FDG-PET in predicting PD-L1 expression in liver metastasis of colon cancer. METHODS: A total of 72 patients with confirmed liver metastasis of colon cancer were included in this retrospective study. The PD-L1 expression and immune cell infiltrating of tumors were determined through immunohistochemistry staining...

Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here, we show, in metastatic CRC preclinical models, that orthotopically implanted primary colon tumors exert a colon-specific antimetastatic effect on distant hepatic lesions. Enterotropic α4β7 integrin-expressing neoantigen-specific CD8 T cells were key components of the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved control of liver lesions by anti-PD-L1 proof-of-concept immunotherapy and generated protective immune memory, whereas partial depletion of α4β7+ cells abrogated control of metastases...

Liver metastasis is the leading cause of death in colorectal cancer. Immunotherapy using immune checkpoint blockade (ICB) is ineffective due to its immunological cold tumor nature. Herein, we prepared a nanodrug (NCG) encapsulating the transforming growth factor-β receptor inhibitor galunisertib (Gal) and the sonosensitizer chlorin e6 (Ce6), which was aimed to turn this type of cold tumor into a hot one to promote the ICB-based immunotherapy against it. After delivery to the tumor, NCG under ultrasonic irradiation generated reactive oxygen species causing tumor immunogenic cell death and releasing immunostimulatory signals such as calreticulin and HMGB1, which increased tumor immunogenicity and activated the innate T lymphocyte immune response...

OBJECTIVE: APC (adenomatous polyposis coli) gene mutation is a central initialization in colon cancer tumorigenesis. However, the connection between APC gene mutation and immunotherapy efficacy for colon cancer remains unknown. This study aimed to explore the impact of APC mutation on immunotherapy efficacy for colon cancer. METHODS: Colon cancer data from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC) were used for the combined analysis...

Primary colon squamous cell carcinoma (SCC) is extremely rare and associated with a poor prognosis. Moreover, there is no treatment guideline for this disease. Proficient mismatch repair/microsatellite-stable (pMMR/MSS) colorectal adenocarcinoma is refractory to immune monotherapy. Although the combination of immunotherapy with chemotherapy in pMMR/MSS colorectal cancer (CRC) is currently under investigation, the clinical activity of this approach in colorectal SCC remains unknown. In this article, we report the case of a pMMR/MSS CRC patient with ascending colon SCC who had high programmed cell death-ligand 1 (PD-L1) expression and the a missense mutation in codon 600 of the B-Raf proto-oncogene (BRAF V600E ) mutation...

Immune checkpoint blockade based on antibodies has shown great clinical success in patients, but the transitory working manner leads to restricted therapeutic benefits. Herein, a genetically engineered adenovirus is developed as the vector to deliver CRISPR/Cas9 (sgCas9-AdV) to achieve permanent PD-L1 gene editing with efficiency up to 78.7% exemplified in Hepa 1-6 liver cancer cells. Furthermore, the sgCas9-AdV is loaded into hydrogel made by silk fiber (SgCas9-AdV/Gel) for in vivo application. The silk-gel not only promotes local retention of sgCas9-AdV in tumor tissue, but also masks them from host immune system, thus ensuring effectively gene transduction over 9 days...

Targeting of the PD-1/PD-L1 immunologic checkpoint is believed to have provided a real breakthrough in the field of cancer therapy in recent years. Due to the intrinsic limitations of antibodies, the discovery of small-molecule inhibitors blocking PD-1/PD-L1 interaction has gradually opened valuable new avenues in the past decades. In an effort to discover new PD-L1 small molecular inhibitors, we carried out a structure-based virtual screening strategy to rapidly identify the candidate compounds. Ultimately, CBPA was identified as a PD-L1 inhibitor with a KD value at the micromolar level...