Abstract
Advancements in monitoring and predicting of patient-specific response of triple negative breast cancer (TNBC) to immunotherapy (IMT) with and without chemotherapy are needed. Using granzyme B-specific positron emission tomography (GZP-PET) imaging, we aimed to monitor changes in effector cell activation in response to IMT with chemotherapy in TNBC. TNBC mouse models received the paclitaxel (PTX) ± immune checkpoint inhibitors anti-programmed death 1 (anti-PD1) and anti-cytotoxic T-lymphocyte 4 (anti-CTLA4). GZP-PET imaging was performed on treatment days 0, 3, and 6. Mean standard uptake value (SUVmean), effector cell fractions, and SUV histograms were compared. Mice were sacrificed at early imaging timepoints for cytokine and histological analyses. GZP-PET imaging data revealed differences prior to tumor volume changes. By day six, responders had SUVmean ≥ 2.2-fold higher (p < 0.0037) and effector cell fractions ≥ 1.9-fold higher (p = 0.03) compared to non-responders. IMT/PTX resulted in a significantly different SUV distribution compared to control, indicating broader distribution of activated intratumoral T-cells. IMT/PTX resulted in significantly more necrotic tumor tissue and increased levels of IL-2, 4, and 12 compared to control. Results implicate immunogenic cell death through upregulation of key Th1/Th2 cytokines by IMT/PTX. Noninvasive PET imaging can provide data on the TNBC tumor microenvironment, specifically intratumoral effector cell activation, predicting response to IMT plus chemotherapy.
Highlights
Further quantitative analysis of granzyme B-specific positron emission tomography (GZP-Positron emission tomography (PET)) images was performed to determine the percentage of effector cells in each tumor region of interest (ROI)
We investigate the direct effects of chemotherapy on granzyme B expression, which is clinically relevant as immunotherapy is often combined with other systemic treatments
The present study provides evidence that GZP-PET imaging may be useful for rapid assessment of combination chemoand immunotherapeutic efficacy in the clinical setting, for triple negative breast cancer (TNBC) patients
Summary
At the time of patient diagnosis, histological reports often detect TNBC tumors when they are high grade (i.e., infiltrating ductal carcinomas) [3]. ROIs were drawn in the left atrium of each subject. ROIs werethe drawn in the atrium of tumor each subject. Cell fracdetermined by quantifying fraction of left voxels in the above Effector background signal, tion was determined by quantifying the fraction of voxels in the tumor above background which was designated as blood measured from the left atrium of the heart Determination of Th1 and Th2 Expressed Cytokine Levels in Serum. Determination of Th1 and Th2 Expressed Cytokine. Serum levels of IFN-γ, IL-2, IL-4, and IL-12 were
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