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The GRP94 Inhibitor PU-WS13 Decreases M2-like Macrophages in Murine TNBC Tumors: A Pharmaco-Imaging Study with 99mTc-Tilmanocept SPECT.

ABSTRACT: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancers and is not eligible for hormone and anti-HER2 therapies. Identifying therapeutic targets and associated biomarkers in TNBC is a clinical challenge to improve patients' outcome and management. High infiltration of CD206+ M2-like macrophages in the tumor microenvironment (TME) indicates poor prognosis and survival in TNBC patients. As we previously showed that membrane expression of GRP94, an endoplasmic reticulum chaperone, was associated with the anti-inflammatory profile of human PBMC-derived M2 macrophages, we hypothesized that intra-tumoral CD206+ M2 macrophages expressing GRP94 may represent innovative targets in TNBC for theranostic purposes. We demonstrate in a preclinical model of 4T1 breast tumor-bearing BALB/c mice that (i) CD206-expressing M2-like macrophages in the TME of TNBC can be specifically detected and quantified using in vivo SPECT imaging with 99mTc-Tilmanocept, and (ii) the inhibition of GRP94 with the chemical inhibitor PU-WS13 induces a decrease in CD206-expressing M2-like macrophages in TME. This result correlated with reduced tumor growth and collagen content, as well as an increase in CD8+ cells in the TME. 99mTc-Tilmanocept SPECT imaging might represent an innovative non-invasive strategy to quantify CD206+ tumor-associated macrophages as a biomarker of anti-GRP94 therapy efficacy and TNBC tumor aggressiveness.

SUBMITTER: Bouchard A

PROVIDER: S-EPMC8699502 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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The GRP94 Inhibitor PU-WS13 Decreases M2-like Macrophages in Murine TNBC Tumors: A Pharmaco-Imaging Study with <sup>99m</sup>Tc-Tilmanocept SPECT.

Bouchard Alexanne A Sikner Hugo H Baverel Valentin V Garnier Anaïs-Rachel AR Monterrat Marie M Moreau Mathieu M Limagne Emeric E Garrido Carmen C Kohli Evelyne E Collin Bertrand B Bellaye Pierre-Simon PS

Cells 20211202 12

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancers and is not eligible for hormone and anti-HER2 therapies. Identifying therapeutic targets and associated biomarkers in TNBC is a clinical challenge to improve patients' outcome and management. High infiltration of CD206<sup>+</sup> M2-like macrophages in the tumor microenvironment (TME) indicates poor prognosis and survival in TNBC patients. As we previously showed that membrane expression of GRP94, an endoplasm ...[more]

PMID: 34943901

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Project description:ImportanceSentinel lymph node biopsy has been proposed as an alternative to up-front elective neck dissection (END) for determination of pathologic nodal status in patients undergoing surgical treatment for oral cavity squamous cell carcinoma (OSCC) with clinically negative neck (cN0). Sentinel lymph node biopsy using current standard tracer agents and imaging adjuncts such as radiolabeled sulfur-colloid and planar lymphoscintigraphy (LS), however, is associated with several drawbacks.ObjectiveTo assess the preliminary utility of technetium Tc 99m (99mTc)-tilmanocept, a novel molecular imaging agent for sentinel lymph node (SLN) mapping, in OSCC.Design, setting, and participantsProspective, nonrandomized, single-arm, part of an ongoing phase 3 clinical trial. Patients had previously untreated, clinically and radiographically node-negative OSCC (T1-4aN0M0) at an academic tertiary referral center.InterventionsPatients received a single dose of 50 µg 99mTc-tilmanocept injected peritumorally followed by dynamic planar LS and fused single-photon emission computed tomography/computed tomography (SPECT/CT) prior to surgery. Surgical intervention consisted of excision of the primary tumor and radioguided SLN dissection followed by planned END. The excised lymph nodes (SLNs and non-SLNs) underwent histopathologic evaluation for presence of metastatic disease.Main outcomes and measuresFalse-negative rate and negative predictive value of SLNB using 99mTc-tilmanocept and comparison of planar LS with SPECT/CT in SLN localization.ResultsTwelve of 20 patients (60%) had metastatic neck disease on pathologic examination. All 12 had at least 1 SLN positive for metastases. No patients had a positive END node who did not have at least 1 positive SLN. These data yield a false-negative rate of 0% and negative predictive value of 100% using 99mTc-tilmanocept in this setting. Dynamic planar LS and SPECT/CT revealed a mean (range) number of hot spots per patient of 2.9 (1-7) and 3.7 (1-12), respectively. Compared with planar LS, SPECT/CT identified additional putative SLNs in 11 of 20 cases (55%).Conclusions and relevanceThe high negative predictive value and low false-negative rate in identification of occult metastases shows 99mTc-tilmanocept to be a promising agent in SLN identification in patients with OSCC. Use of SPECT/CT improves preoperative SLN localization including delineation of SLN locations near the primary tumor when compared with planar LS imaging.Trial registrationclinicaltrials.gov Identifier: NCT00911326.

Project description:A well-established approach for diagnostic imaging of osteomyelitis (OM), a bone infection, is simultaneous SPECT-CT of 99mTc sulfur colloid (SC) and 111In white blood cells (WBC). This method provides essentially perfect spatial registration of the tracers within anatomic sites of interest. Currently, diagnosis is based purely on a visual assessment-where relative discordance between 99mTc and 111In uptake in bone, i.e., high 111In and low 99mTc, suggests OM. To achieve more quantitative images, noise, scatter, and crosstalk between radionuclides must be addressed through reconstruction. Here the authors compare their Monte Carlo-based joint OSEM (MC-JOSEM) algorithm, which reconstructs both radionuclides simultaneously, to a more conventional triple-energy window-based reconstruction (TEW-OSEM), and to iterative reconstruction with no compensation for scatter (NC-OSEM).The authors created numerical phantoms of the foot and torso. Multiple bone-infection sites were modeled using high-count Monte Carlo simulation. Counts per voxel were then scaled to values appropriate for 111In WBC and 99mTc SC imaging. Ten independent noisy projection image sets were generated by drawing random Poisson deviates from these very low-noise images. Data were reconstructed using the two iterative scatter-compensation methods, TEW-OSEM and MC-JOSEM, as well as the uncorrected method (NC-OSEM). Mean counts in volumes of interest (VOIs) were used to evaluate the bias and precision of each method. Data were also acquired using a phantom, approximately the size of an adult ankle, consisting of regions representing infected and normal bone marrow, within a bone-like attenuator and surrounding soft tissue; each compartment contained a mixture of 111In and 99mTc. Low-noise data were acquired during multiple short scans over 29 h on a Siemens Symbia T6 SPECT-CT with medium-energy collimators. Pure 99mTc and 111In projection datasets were derived by fitting the acquired projections to the sum of 99mTc and 111In contributions, using the known half-lives. Uncontaminated data were scaled and recombined into six datasets with different activity ratios; ten Poisson noise realizations were then generated for each ratio. VOIs in each of the compartments were used to evaluate the bias and precision of each method with respect to reconstructions of uncontaminated datasets. In addition to the simulated and acquired phantom images, the authors reconstructed patient images with MC-JOSEM and TEW-OSEM. Patient reconstructions were assessed qualitatively for lesion contrast, spatial definition, and scatter.For all simulated and acquired infection phantoms, the root-mean squared-error of measured 99mTc activity was significantly improved with MC-JOSEM and TEW-OSEM in comparison to NC-OSEM reconstructions. While MC-JOSEM trended toward outperforming TEW-OSEM, the improvement was only found to be significant (p<0.001) for the acquired bone phantom in which a wide range of 111In∕99mTc concentration ratios were tested. In all cases, scatter correction did not significantly improve 111In quantitation.Compensation for scatter and crosstalk is useful for improving quality, bias, and precision of 99mTc activity estimates in simultaneous dual-radionuclide imaging of OM. The use of the more rigorous MC-based estimates provided marginal improvements over TEW. While the phantom results were encouraging, more subjects are needed to evaluate the usefulness of quantitative 111In∕99mTc SPECT-CT in the clinic.

Dataset Information

The GRP94 Inhibitor PU-WS13 Decreases M2-like Macrophages in Murine TNBC Tumors: A Pharmaco-Imaging Study with 99mTc-Tilmanocept SPECT.

Publications

The GRP94 Inhibitor PU-WS13 Decreases M2-like Macrophages in Murine TNBC Tumors: A Pharmaco-Imaging Study with <sup>99m</sup>Tc-Tilmanocept SPECT.

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