Intravoxel Incoherent Motion Diffusion-weighted MR Imaging for Monitoring the Immune Response of Immunogenic Chemotherapy

Background: Traditional chemotherapeutic drugs have the potential to increase tumor cell immunogenicity by activating immunogenic cell death (ICD). The accumulation of preclinical and clinical evidence suggests that the success of neoadjuvant chemotherapy, immunogenic chemotherapy depends (at least in part) on their ability to stimulate anti-cancer immune responses. Although the pathological examination is the gold standard for detecting the antitumor immune response, it is invasive and cannot be performed repetitively. Hence, the aim of our study was to evaluate the predictive value of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in the quantitative assessment of conventional chemotherapy-activated immune responses in mouse tumor models and clinics.Methods: A total of 19 subcutaneous tumor-bearing mice were randomly divided into treated and control groups. Both groups had orderly IVIM DWI examinations before and on days 6 and 12 after the administration of cyclophosphamide (CPA) or saline. The expressions of immune-related genes in the tumor were measured by qPCR or detected by immunohistochemical assay. In addition, six patients with breast cancer requiring neoadjuvant chemotherapy also underwent functional MRI examinations. The primary statistical analysis methods were the Wilcoxon test of variance, correlation analysis, and the Kruskal-Wallis H test.Results: The tumoral pseudodiffusion coefficient (D*), the perfusion fraction (f), and the blood flow-related parameter (fD*) of the treatment group showed a trend that significantly decreased on day 6. Then, these values increased on day 12, while they displayed the opposite tendency in the control group. Compared with the control group, a strong induction of the expression of the immune responses in the CPA treatment group was observed on day 12. Additionally, the changes in functional MRI parameters in the six patients with breast cancer after neoadjuvant chemotherapy showed similar trends to those in the tumor-bearing mice in the CPA treatment group.Conclusions: The immune response induced by immunogenic chemotherapy could be effectively evaluated using IVIM-DWI. The D and D* values could be potential, sensitive imaging markers for identifying the antitumor immune response initiated by immunogenic chemotherapy.