Peptide Alarm Therapy: A Novel Approach to overcome Immunosuppressive Tumor Microenvironments

An immunosuppressive tumor microenvironment is one of the major challenges for existing immunotherapies. A novel form of immunotherapy, known as peptide alarm therapy (PAT), has shown promise in activating the immune system within tumors by injecting viral peptides. Pamela C. Rosato and her team at the Center for Immunology of the University of Minnesota in Minneapolis, USA, have already demonstrated the effectiveness of peptide alarm therapy in reducing the growth of checkpoint blockade-resistant tumors in melanoma mouse models. Using virus-specific peptides such as GLCTLVAML, CLGGLLTMV, NLVPMVATV, and GILGFVFTL, the researchers have then investigated the extent to which peptide alarm therapy can be applied to treatment-resistant glioblastoma multiforme.

Peptide alarm therapy activates virus-specific CD8+ T memory cells that remain vigilant throughout the body after an infection and are also present in tumors. They patrol the tissue for signs of new infections, and rarely return to the bloodstream. When exposed to antigens again, they produce pro-inflammatory cytokines and chemokines. In this way, they trigger local immune stimulation and recruit innate and adaptive immunity to the affected tissue.

Peptide alarm therapy reduced growth of resistant melanoma tumors

Scientists have already successfully reactivated virus-specific T memory cells in a melanoma mouse model by injecting adjuvant-free, non-replicating viral peptides into the tumors. [1] This approach successfully reduced the growth of melanoma tumors that were resistant to checkpoint blockade and had poor immunogenicity. When the scientists combined the tumor alarm therapy with a PD-L1 checkpoint blockade, they were able to completely eliminate the melanoma tumor load.

Building on this success, the researchers investigated the potential of using viral peptides to reactivate T memory cells in glioblastoma multiforme – one of the most aggressive and treatment-resistant forms of cancer. [2] Despite standard treatments such as surgery, radiation, and chemotherapy, glioblastoma multiforme is invariably fatal. The immune system is locally and systemically suppressed in glioblastoma multiforme, making it difficult for immunotherapies that work in other tumor types to be effective.

Presence of Virus-Specific CD8+ T Cells in Glioblastoma Tumors

To investigate the presence of virus-specific CD8+ T cells in human glioblastomas, the researchers obtained tumor tissue from patients who underwent surgical resection of solid tumors or tumor metastases. They isolated lymphocytes from the minced tumors and constructed HLA-A*02:01-specific tetramers loaded with the following immunodominant peptides from common viral infections:

• GLCTLVAML and CLGGLLTMV from Epstein-Barr virus
• NLVPMVATV from cytomegalovirus
• GILGFVFTL from influenza A virus

The lymphocytes were stained with the PE-conjugated HLA-A*02 tetramers for each of these viral epitopes. The results showed that virus-specific CD8+ T cells were present in all clinical glioblastoma samples examined. Notably, T cells specific for a single viral epitope often accounted for more than 1% of the total CD8+ T cell population in the tumor. The detected memory T cells expressed markers of tissue residency (CD69 and CD103).

Immunodominant Viral Peptides Reactivate Memory T Cells

The researchers then tested whether they could reactivate the virus-specific T cells in glioblastoma tumors to enable them to assume sensor and alarm functions, thereby reversing the immunosuppressive tumor microenvironment. To this end, they created ex vivo organotypic slice cultures from five HLA-A2 + glioblastoma tumors, preserving the tumor environment. The scientists added the viral peptides GLCTLVAML, CLGGLLTMV, NLVPMVATV, and GILGFVFTL or a control to the autologous slice cultures. Nine hours later, they removed the tumor slices and performed RNAseq on the entire tissue. In 4 of the 5 tumors, gene expression differed significantly between control and viral peptide treatment. Further analysis revealed that functions and signaling pathways crucial for antiviral reactions and lymphocyte migration were upregulated.

Conclusion: Peptide alarm therapy triggers immune stimulation

Virus-specific memory T cells play a crucial role in the immunological microenvironment of glioblastoma. By reactivating these cells with immunodominant peptides from common viral infections, it is possible to harness their activity to overcome the immunosuppressive tumor microenvironment. This study highlights the potential of virus-specific tissue-resident memory T cells for improving treatment outcomes in patients with glioblastoma multiforme.

Literature:

1. Rosato, Pamela C et al. “Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy.” Nature communications vol. 10,1 567. 4 Feb. 2019, doi:10.1038/s41467-0
2. Ning, Jianfang et al. “Functional virus-specific memory T cells survey glioblastoma.” Cancer immunology, immunotherapy : CII vol. 71,8 (2022): 1863-1875. doi:10.1007/s00262-021-03125-w