Radiation and Cancer Biology

SS 05 - Biology 2 - Radiation and Immune Response Session I

52 - Tryptophan Metabolism Contributes to Radiation-Induced Immune Checkpoint Reactivation in Glioblastoma

Sunday, October 21
5:55 PM - 6:05 PM
Location: Room 007 C/D

Tryptophan Metabolism Contributes to Radiation-Induced Immune Checkpoint Reactivation in Glioblastoma
P. Kesarwani1, A. Prabhu1, S. Kant1, P. Kumar1, S. Graham1, K. Buelow1, G. D. Wilson2, and P. Chinnaiyan2; 1Beaumont Health, Royal Oak, MI, 2Beaumont Health (Department of Radiation Oncology), Royal Oak, MI

Purpose/Objective(s): Immune checkpoint inhibitors designed to revert tumor-induced immune suppression have emerged as potent anti-cancer therapies. The potential of radiation (RT) to stimulate an immune response and work synergistically with immune checkpoint agents offers strong promise in enhancing therapeutic response. Tryptophan metabolism represents an important immune checkpoint and targeting this pathway’s rate limiting enzyme indoleamine 2,3-dioxygenase (IDO1) is actively being investigated clinically. Here, through integrated cross-platform analyses, we studied this metabolic node in GBM and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with RT.

Materials/Methods: LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma. Immune competent mice (C57BL/6) were injected orthotopically with genetically engineered murine glioma cells. After verifying successful implant via MRI, mice were treated with GDC-0919 (200 mg/kg BID), both alone or in combination with RT (6Gyx1 or hypofractionated RT (hfRT; 6Gyx3). Correlative studies designed to determine the immune consequences of individual treatments were performed on isolated tumors using flow cytometry and western blot. Pharmacodynamic studies were performed to evaluate blood brain barrier (BBB) penetrance of GDC-0919 using LC-MS.

Results: Integrated cross-platform analyses coupling global metabolomic and gene-expression profiling in patient-derived gliomas (n=108) identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of GBM, which was recapitulated in our preclinical models. GDC-0919 demonstrated potent inhibition of this node in a diverse panel of GBM lines and importantly, effectively crossed the BBB. Although GDC-0919 as a single agent did not demonstrate anti-tumor activity, it had a strong potential for enhancing RT response in GBM, which was further augmented when using a hfRT regimen (p<0.005). Evaluation of isolated tumors demonstrated that hfRT response in GBM involves both immune stimulation, reflected by a ~50% increase in activated (CD8+CD69+) and ~30% increase in cytotoxic (CD8+Granzyme B+) Tcells, which was balanced by immune checkpoint reactivation, reflected by an increase in IDO1 expression and a 2x increase in regulatory Tcells (Tregs). GDC-0919 mitigated RT-induced Tregs and enhanced activated and cytotoxic Tcells when compared to hfRT alone.

Conclusion: Although hfRT stimulates an immune response, it is balanced by immune checkpoint reactivation and suppression. Tryptophan metabolism/IDO1 signaling represents a metabolic node in GBM and is involved in RT-induced checkpoint reactivation. Combining hfRT with IDO1 inhibition enhances therapeutic response in GBM by mitigating RT-induced immune suppression, providing rationale for further clinical testing.

Author Disclosure: P. Kesarwani: None. A. Prabhu: None. S. Kant: None. P. Kumar: None. G.D. Wilson: None. P. Chinnaiyan: None.

Pravin Kesarwani, PhD

Willam Beaumont Resarch Institute

Disclosure:
No relationships to disclose.

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