Establishing Imaging Biomarkers of Host Immune System Efficacy during Glioblastoma Therapy Response: Challenges, Obstacles and Future Perspectives

Abstract

This hypothesis proposal addresses three major questions: (1) Why do we need imaging biomarkers for assessing the efficacy of immune system participation in glioblastoma therapy response? (2) Why are they not available yet? and (3) How can we produce them? We summarize the literature data supporting the claim that the immune system is behind the efficacy of most successful glioblastoma therapies but, unfortunately, there are no current short-term imaging biomarkers of its activity. We also discuss how using an immunocompetent murine model of glioblastoma, allowing the cure of mice and the generation of immune memory, provides a suitable framework for glioblastoma therapy response biomarker studies. Both magnetic resonance imaging and magnetic resonance-based metabolomic data (i.e., magnetic resonance spectroscopic imaging) can provide non-invasive assessments of such a system. A predictor based in nosological images, generated from magnetic resonance spectroscopic imaging analyses and their oscillatory patterns, should be translational to clinics. We also review hurdles that may explain why such an oscillatory biomarker was not reported in previous imaging glioblastoma work. Single shot explorations that neglect short-term oscillatory behavior derived from immune system attack on tumors may mislead actual response extent detection. Finally, we consider improvements required to properly predict immune system-mediated early response (1–2 weeks) to therapy. The sensible use of improved biomarkers may enable translatable evidence-based therapeutic protocols, with the possibility of extending preclinical results to human patients.

Correlation of MR-Based Metabolomics and Molecular Profiling in the Tumor Microenvironment of Temozolomide-Treated Orthotopic GL261 Glioblastoma in Mice

“…Investigation on human GB patients demonstrated expression of proteases ADAM8, 10, and 17, and MMP9 and 14, which are associated with the occurrence of GAMs and support their functions, e.g., shedding of EGF-R by ADAM17 can direct cancer cell invasion [64], ADAM10 can regulate macrophage survival [65], whereas ADAM8 in macrophages increases MMP9 levels in co-cultured tumor cells [66] so that these ADAM proteases are associated with GAM functions and directly affect the nature of the TME [67,68]. Within the TME, all ADAM proteases investigated here (8,10,17) are expressed not only in cancer but also in tumor-infiltrating immune cells, again suggesting that they are part of tumor-immune cell communication.…”

“…In particular, metabolomics is known to produce earlier and more confident information about events related to therapy in preclinical GB models [7]. Thus, local changes during GB therapy triggered by changes in the TME may be spotted by non-invasive approaches, such as MRSI, providing potential clues about efficient tumor elimination by the host immune system, thereby producing potential surrogate biomarkers with oscillatory frequency [8][9][10] matching the immune cycle length. As a major immune cell type in the TME, glioma-associated microglia/macrophages (GAMs) can present various subtypes with a simplified categorization into either pro-inflammatory anti-tumor (M1) or pro-tumor (M2) phenotypes.…”

Imaging and Spectroscopic-Based Methods to Understand Cancer Metabolism and Biology

“…The present Special Issue contains four reviews [ 1 , 2 , 3 , 4 ] and four research articles [ 5 , 6 , 7 , 8 ] with the original work covering a wide range of methods that can be applied to assess and measure several characteristics of tumours.…”

“…Prof Arús and Dr Candiota reviewed the status of imaging biomarkers for assessing the efficacy of immune system participation in glioblastoma therapy response and addressed the questions as to the means with which to produce them [ 1 ]. However, such biomarkers are not yet available, and current follow-up approaches for patients with glioblastoma are mostly based on MR imaging criteria or other approaches such as PET, which may overlook the information related to immune system oscillations.…”

“…Deuterium metabolic imaging (DMI) has strong potential to become a dominant MR research tool and a viable clinical imaging modality to map metabolism with high temporal and/or spatial resolution in oncology. The present Special Issue contains four reviews [1][2][3][4] and four research articles [5][6][7][8] with the original work covering a wide range of methods that can be applied to assess and measure several characteristics of tumours.…”