PD-1 blockade enhances the vaccination-induced immune response in glioma
Joseph P Antonios1, Horacio Soto1, Richard G Everson1
1Department of Neurosurgery, David Geffen School of Medicine at UCLA, UCLA, Los Angeles, California, USA.
Abstract:
DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD-1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor- bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8+ T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy.
Insights
Combining dendritic cell (DC) vaccination with PD-1 blockade significantly improves survival in glioblastoma (GBM) models by enhancing CD8+ T cell responses. This combination therapy overcomes immune resistance in established tumors.
Area of Science:
- Immunology
- Oncology
- Neuro-oncology
Background:
- Dendritic cell (DC) vaccination shows promise for glioblastoma (GBM) but has limited efficacy in established tumors.
- Negative costimulatory pathways, like programmed death 1/programmed death ligand 1 (PD-1/PD-L1), are implicated in immune resistance within tumors.
- Clinical responses to PD-1 pathway inhibition are variable.
Purpose of the Study:
- To investigate the efficacy of combining DC vaccination with PD-1 blockade in established intracranial glioma models.
- To determine the role of CD8+ T cells in the observed survival benefit.
- To explore the impact of this combination therapy on tumor-infiltrating lymphocytes (TILs) and clinical GBM samples.
Main Methods:
- Treatment of intracranial glioma-bearing mice with DC vaccination and/or PD-1 blockade.
- Assessment of survival rates and CD8+ T cell dependence.
- Analysis of TIL markers, including integrin homing and immunologic memory.
- Evaluation of PD-1 expression and blockade effects on TILs from GBM patients.
Main Results:
- Combination therapy of DC vaccination and PD-1 blockade led to long-term survival in mice with established tumors, whereas single agents did not.
- The survival benefit was entirely dependent on CD8+ T cells.
- Combined treatment upregulated integrin homing and immunologic memory markers on TILs.
- In GBM patients, DC vaccination increased PD-1 expression, and ex vivo PD-1 blockade enhanced TIL-mediated tumor cell killing.
Conclusions:
- The PD-1/PD-L1 pathway is crucial in mediating adaptive immune resistance in established GBM following active vaccination.
- Combining DC vaccination with PD-1 blockade offers a rationale for clinical translation in glioblastoma treatment.
- This combination strategy enhances anti-tumor T cell responses and overcomes immune evasion mechanisms.
