ID #461 Loss of Macrophage Migration Inhibitory Factor (MIF) Receptor CD74 following Irradiation and Bone Marrow Transplant Impairs Malignant Progression in an AYA Preclinical Model of Glioma
Sakthi Rajendran, Susobhan Sarkar, Daniel Kreatsoulas, Wesley Wang, Justin Lathia, Richard Bucala, Prajwal RajappaAbstract
Introduction
As gliomas progress, CD74/MIF signaling promotes immunosuppressive myeloid cell accumulation and correlates with poor survival, while downregulation of CD74 is associated with increased CD8+ T cell recruitment and a better prognosis. MIF and CD74 are upregulated in tumor infiltrating bone marrow-derived myeloid cells (BMDM)s in vivo, thus interrogation of CD74/MIF signaling in BMDMs may identify potential therapeutic strategies to reprogram immunosuppressive myeloid cell phenotypes.
Methods
We pursued CD74-knockout (CD74KO) bone marrow transplant (BMT) following whole body irradiation (9.5Gy) (IR) with cranial sparing in an RCAS/PDGF-β driven preclinical model of glioma malignant progression and performed spatial transcriptomic profiling during distinct timepoints of tumor progression.
Results
During spatial tumor microenvironment (TME) evaluation of earlier time points of low-grade glioma (LGG), we observed an upregulation of myeloid markers (CD45, CD11c), antigen presentation (MHCII), T cell co-stimulatory molecules (CD28, OX40L), and immune checkpoints (CTLA4, B7H3, VISTA) in CD74KO mice. However, in CD74 intact mice, we observed expression of T cell exhaustion markers (TIM3 and LAG3) and markers associated with T regulatory cells (FOXP3+), checkpoints (CTLA4, PD-L1, PD-1), underscoring T cell dysregulation programs. At later LGG timepoints prior to malignant progression, we observed expression of T cell checkpoint (PDL1, B7H3 and VISTA) and exhaustion markers (TIM3) in CD74 intact tumor bearing animals and patients, suggesting dynamically evolving immunosuppressive programs that potentiate glioma malignant progression. Also, when tumor cells were segmented within the tumor core and perivascular regions of CD74 intact mice, they expressed markers of T cell checkpoint (PDL1), exhaustion (LAG3), and decreased costimulatory molecules (OX40L), contributing to immune dysregulation. Functionally, CD74 KO animals demonstrated a significant overall survival advantage compared to wildtype animals.
Conclusion
Irradiation and BMT of CD74KO bone marrow in a preclinical model of glioma malignant progression provided a significant survival benefit while stimulating the innate and adaptive immune microenvironment.