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Immune Escape After Adoptive T-cell Therapy for Malignant Gliomas
Tyler J Wildes1, Kyle A Dyson1, Connor Francis1
1University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, Florida.
Purpose:
Immunotherapy has been demonstrably effective against multiple cancers, yet tumor escape is common. It remains unclear how brain tumors escape immunotherapy and how to overcome this immune escape.
Experimental Design:
We studied KR158B-luc glioma-bearing mice during treatment with adoptive cellular therapy (ACT) with polyclonal tumor-specific T cells. We tested the immunogenicity of primary and escaped tumors using T-cell restimulation assays. We used flow cytometry and RNA profiling of whole tumors to further define escape mechanisms. To treat immune-escaped tumors, we generated escape variant-specific T cells through the use of escape variant total tumor RNA and administered these cells as ACT. In addition, programmed cell death protein-1 (PD-1) checkpoint blockade was studied in combination with ACT.
Results:
Escape mechanisms included a shift in immunogenic tumor antigens, downregulation of MHC class I, and upregulation of checkpoint molecules. Polyclonal T cells specific for escape variants displayed greater recognition of escaped tumors than primary tumors. When administered as ACT, these T cells prolonged median survival of escape variant-bearing mice by 60%. The rational combination of ACT with PD-1 blockade prolonged median survival of escape variant glioma-bearing mice by 110% and was dependent upon natural killer cells and T cells.
Conclusions:
These findings suggest that the immune landscape of brain tumors are markedly different postimmunotherapy yet can still be targeted with immunotherapy.
Insights
Brain tumors can evade immunotherapy through antigen shifts and molecule changes. New T-cell therapies targeting these escape variants, especially combined with PD-1 blockade, significantly improve survival in mice.
Area of Science:
- Neuro-oncology
- Immunology
- Cancer Research
Background:
- Immunotherapy shows promise in cancer treatment but faces challenges with tumor immune escape.
- Mechanisms of immune escape in brain tumors remain poorly understood.
- Overcoming immunotherapy resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate how brain tumors escape immunotherapy.
- To develop strategies to overcome immunotherapy resistance in gliomas.
- To evaluate novel adoptive cellular therapy (ACT) approaches.
Main Methods:
- Studied glioma-bearing mice treated with adoptive cellular therapy (ACT).
- Analyzed tumor immunogenicity, flow cytometry, and RNA profiling to identify escape mechanisms.
- Generated and administered escape variant-specific T cells and combined ACT with PD-1 blockade.
Main Results:
- Identified escape mechanisms including antigen shifts, MHC class I downregulation, and checkpoint molecule upregulation.
- T cells targeting escape variants showed enhanced recognition and prolonged survival by 60% in mice.
- Combination of ACT and PD-1 blockade extended median survival by 110%, dependent on NK and T cells.
Conclusions:
- Brain tumor immune landscapes change post-immunotherapy but remain targetable.
- Tailored immunotherapy, including ACT and checkpoint blockade, can overcome tumor immune escape.
- Findings provide a basis for developing new brain tumor treatment strategies.
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