Visualizing the dynamics of checkpoint protein IDO1 reveals host antitumor responses activated by a combination of immunotherapy and chemotherapy with 11C-L-1MTrp PET

Background and Aims: Capturing host antitumor responses to combinatorial immunotherapy remains a major challenge. From the standpoint of immunology, cancer immunotherapy is considered as a “double edged sword” in that it can trigger two opposite immunologic processes to limit potential toxicity associated with excessive response [1]. So tracking its opposite immune regulatory-mechanisms has potential as surrogates for defining the complex scenarios. In this study, we developed a small-molecular positron emission tomography/computed tomography (PET/CT) method targeting the checkpoint protein, IDO1, in tumor-bearing hosts to address this challenge. \nMethods: Leveraging the very short-lived positron emitter carbon-11 (11C; half-life: 20.4 min) to label a small molecule IDO1 inhibitor, levorotary (L) form of 1-methyl-tryptophan (1MTrp), we developed a radioprobe 1-N-11C-methyl-L-tryptophan (11C-L-1MTrp) [2]. Using PET/CT with 11C-L-1MTrp, we specifically and serially monitored IDO1 changes to reveal the antitumor immune response in melanoma-bearing immunocompetent mice treated with immunotherapy combinatorial chemotherapy. Animal studies were approved by the Animal Ethics Committee of the National Institutes for Quantum and Radiological Science and Technology.\nResults: On combining the 11C-L-1MTrp and the imaging power of PET/CT, we observed that IDO1 exhibited dynamic alterations in mesenteric lymph nodes (MLN) and the caput of the epididymis, and observed a connection between active responses to combinatorial immunotherapy in immunocompetent mice. These imaging markers exhibited an empirical cut-off value of 7.023 %ID/g for radioactivity in MLN, which provided an early-on-treatment indicator with 97.92 % specificity. A cut-off value of 8.313 %ID/g in the epididymis offered a sensitivity of 100 % as an index of immune exhaustion. \nConclusion: 11C-L-1MTrp-PET/CT provided a visual method to capture the dynamics of host responses to combinatorial immunotherapies, with near-term clinical application. \nReferences: [1]. Pardoll DM. Nature Rev. Cancer. 2012, 12, 252. [2] Xie, L. et al. Sci. Rep.2015, 5,16417.12th World Congress of the World Federation of Nuclear Medicine and Biolog