Carbonic Anhydrase IX—Mouse versus Human

Takáčová, Martina; Baráthová, Monika; Zaťovičová, Miriam; Golias, Tereza; Kajanová, Ivana; Jelenska, Lenka; Sedlakova, Olga; Švastová, Eliška; Kopáček, Juraj; Pastoreková, Silvia

doi:10.3390/ijms21010246

Cited by 7 publications

(3 citation statements)

References 50 publications

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“…Significantly higher uptake of [ 111 In]In-MSC3 compared to irrelevant [ 111 In]In-hIgG1 in several organs suggests CAIX-mediated uptake. CAIX expression in the mouse gastrointestinal tract has been described as well as mild expression in the lungs, kidneys, pancreas, liver, and spleen. , Over time, [ 111 In]In-MSC3 clears from the blood and other tissues, resulting in a lower background signal. Despite this, we decided to image at 24 h post tracer injection because of the growth characteristics of our model systems.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Imaging of Hypoxic CAIX-Positive Tumor Areas with Low Immune Cell Infiltration in Syngeneic Mouse Tumor Models

et al. 2023

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Limited diffusion of oxygen in combination with increased oxygen consumption leads to chronic hypoxia in most solid malignancies. This scarcity of oxygen is known to induce radioresistance and leads to an immunosuppressive microenvironment. Carbonic anhydrase IX (CAIX) is an enzyme functioning as a catalyzer for acid export in hypoxic cells and is an endogenous biomarker for chronic hypoxia. The aim of this study is to develop a radiolabeled antibody that recognizes murine CAIX to visualize chronic hypoxia in syngeneic tumor models and to study the immune cell population in these hypoxic areas. An anti-mCAIX antibody (MSC3) was conjugated to diethylenetriaminepentaacetic acid (DTPA) and radiolabeled with indium-111 (111In). CAIX expression on murine tumor cells was determined using flow cytometry, and in vitro affinity of [111In]In-MSC3 was analyzed in a competitive binding assay. Ex vivo biodistribution studies were performed to determine in vivo radiotracer distribution. CAIX+ tumor fractions were determined by mCAIX microSPECT/CT, and the tumor microenvironment was analyzed using immunohistochemistry and autoradiography. We showed that [111In]In-MSC3 binds to CAIX-expressing (CAIX+) murine cells in vitro and accumulates in CAIX+ areas in vivo. We optimized the use of [111In]In-MSC3 for preclinical imaging such that it can be applied in syngeneic mouse models and showed that we can quantitatively distinguish between tumor models with varying CAIX+ fractions by ex vivo analyses and in vivo mCAIX microSPECT/CT. Analysis of the tumor microenvironment identified these CAIX+ areas as less infiltrated by immune cells. Together these data demonstrate that mCAIX microSPECT/CT is a sensitive technique to visualize hypoxic CAIX+ tumor areas that exhibit reduced infiltration of immune cells in syngeneic mouse models. In the future, this technique may enable visualization of CAIX expression before or during hypoxia-targeted or hypoxia-reducing treatments. Thereby, it will help optimize immuno- and radiotherapy efficacy in translationally relevant syngeneic mouse tumor models.

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Section: Discussionmentioning

confidence: 99%

Quantitative Imaging of Hypoxic CAIX-Positive Tumor Areas with Low Immune Cell Infiltration in Syngeneic Mouse Tumor Models

et al. 2023

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“…Few studies have reported the relationship between CA-IX and sEVs in different cancer types [ 44 , 45 , 46 , 47 ]. For the first time, we investigated CA-IX protein expression associated with sEVs in melanoma in vitro models.…”

Section: Introductionmentioning

confidence: 99%

CA-IX-Expressing Small Extracellular Vesicles (sEVs) Are Released by Melanoma Cells under Hypoxia and in the Blood of Advanced Melanoma Patients

Venturella

Falsini

Coppola

et al. 2023

IJMS

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Cutaneous melanoma is a highly aggressive skin cancer, with poor prognosis. The tumor microenvironment is characterized by areas of hypoxia. Carbonic anhydrase IX (CA-IX) is a marker of tumor hypoxia and its expression is regulated by hypoxia-inducible factor-1 (HIF-1). CA-IX has been found to be highly expressed in invasive melanomas. In this study, we investigated the effects of hypoxia on the release of small extracellular vesicles (sEVs) in two melanoma in vitro models. We demonstrated that melanoma cells release sEVs under both normoxic and hypoxic conditions, but only hypoxia-induced sEVs express CA-IX mRNA and protein. Moreover, we optimized an ELISA assay to provide evidence for CA-IX protein expression on the membranes of the sEVs. These CA-IX-positive sEVs may be exploited as potential biomarkers for liquid biopsy.

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“…This process results in HIF-1α accumulation and subsequent dimerization with HIF-1β, activating the transcription of several hypoxia response genes, including CAIX [4]. A mutation in the pVHL-coding gene present in about 95% of clear cell renal carcinoma (ccRCC) cases can also be responsible for HIF-1α accumulation, leading to the CAIX constitutive expression found in this cancer type [5][6][7]. In addition to tumors, CAIX expression is restricted to a few healthy tissues, such as intrahepatic biliary ducts, gastric mucosa, and duodenum [8], highlighting its potential for developing cancer-targeted therapies.…”

Section: Introductionmentioning

confidence: 99%

Carbonic Anhydrase IX: A Renewed Target for Cancer Immunotherapy

Campos

Souza

Silva

et al. 2022

Cancers

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The carbonic anhydrase isoform IX (CAIX) enzyme is constitutively overexpressed in the vast majority of clear cell renal cell carcinoma (ccRCC) and can also be induced in hypoxic microenvironments, a major hallmark of most solid tumors. CAIX expression is restricted to a few sites in healthy tissues, positioning this molecule as a strategic target for cancer immunotherapy. In this review, we summarized preclinical and clinical data of immunotherapeutic strategies based on monoclonal antibodies (mAbs), fusion proteins, chimeric antigen receptor (CAR) T, and NK cells targeting CAIX against different types of solid malignant tumors, alone or in combination with radionuclides, cytokines, cytotoxic agents, tyrosine kinase inhibitors, or immune checkpoint blockade. Most clinical studies targeting CAIX for immunotherapy were performed using G250 mAb-based antibodies or CAR T cells, developed primarily for bioimaging purposes, with a limited clinical response for ccRCC. Other anti-CAIX mAbs, CAR T, and NK cells developed with therapeutic intent presented herein offered outstanding preclinical results, justifying further exploration in the clinical setting.

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Carbonic Anhydrase IX—Mouse versus Human

Cited by 7 publications

References 50 publications

Quantitative Imaging of Hypoxic CAIX-Positive Tumor Areas with Low Immune Cell Infiltration in Syngeneic Mouse Tumor Models

Quantitative Imaging of Hypoxic CAIX-Positive Tumor Areas with Low Immune Cell Infiltration in Syngeneic Mouse Tumor Models

CA-IX-Expressing Small Extracellular Vesicles (sEVs) Are Released by Melanoma Cells under Hypoxia and in the Blood of Advanced Melanoma Patients

Carbonic Anhydrase IX: A Renewed Target for Cancer Immunotherapy

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