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Tumor-specific T cells play a crucial role in anti-tumor immunity and are the target of cancer immunotherapy. However, these cells are scarce and functionally depleted in the tumor microenvironment (TME), resulting in ineffective immunotherapy in most cancer patients. In contrast, emerging evidence suggests that tumor-independent bystander T cells (TBYS) are abundant and maintain functional memory properties in the TME.
On April 12, 2024, Ye Lilin from Army Medical University, Zhang Guozhong from China Agricultural University, Bai Fan from Peking University, and Li Yan from Nanjing University jointly published a joint newsletter entitled "An oncolytic virus delivering tumor-irrelevant bystander T cell epitopes induces anti-tumor immunity and" in Nature Cancer Online potentiates cancer immunotherapy", which designed an oncolytic virus (OV) encoding a TBYS epitope (OV-byte) to specifically transfer antigens from tumor cells to pre-existing TBYS cells, thereby achieving effective tumor suppression in multiple preclinical models.
Mechanistically, OV-BYTE induces epitope spread of tumor antigens to elicit a more diverse tumor-specific T cell response. Notably, the OV-BYTE strategy targeting human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory effectively inhibited tumor progression in a human tumor cell-derived xenograft model, providing important insights for improving cancer immunotherapy in a large population with a history of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination.
After acute infection or vaccination, memory T (TMEM) cells form and provide long-term protection against cognate pathogens. In contrast, T cell failure has been well characterized in many chronic infections and cancers. Tumor-infiltrating CD8+ T cells that specifically recognize tumor antigens exhibit a typical exhaustion-associated phenotype, including a gradual loss of effector function, proliferative capacity, and memory potential, along with elevated and sustained expression of a panel of inhibitory immune checkpoint receptors (e.g., PD-1, CTLA-4, and TIM-3). Blocking antibodies against these inhibitory immune checkpoint receptors, called immune checkpoint blockade (ICB), can rejuvenate the depleted CD8+ T (TEX) cells in the TME, thereby revitalizing the CD8+ T (TEX) cells in the TME, laying the foundation for the clinical efficacy of ICB. Although ICB therapies targeting PD-1 programmed cell death ligand 1 (PD-L1) interactions have resulted in durable responses in a subset of cancer patients, overall response rates have remained modest or even indolent in some cancer types, which may be explained in part by the fact that ICB therapy did not fundamentally alter the epigenetic program of depletion in TEX cells, nor did it reprogram these cells to differentiate into TMEM cells. Accumulating evidence suggests that the specific recognition of tumor-derived antigens is limited to a small subset of tumor-infiltrating T cells, while the vast majority of tumor-infiltrating T cells recognize tumor-independent antigens, particularly common viral antigens, and are therefore defined as "TBYS cells". Tumor-infiltrating TBYS cells have been reported to exhibit a tmem-associated phenotype; However, their detailed differentiation status is not well characterized. In particular, it is unclear whether CD8+ TBYS cells and CD4+ cells have similar memory signatures in the TME. In addition, since the number and function of TME TBYS cells far exceeds that of tumor-specific TEX cells, there would be great therapeutic value if orthotopic TBYS cells could be reused to eliminate tumor cells.
OV-BYTE治疗的抗肿瘤作用归因于病毒特异性CD8+和CD4+ TBYS细胞（Credit: Nature Cancer）
OV is a highly versatile platform that can deliver a variety of payloads into tumor cells. A number of DNA or RNA viruses with strong tumorigenicity have been proposed as vectors for OV immunotherapy, such as herpes simplex virus (HSV), adenovirus, and Newcastle disease virus (NDV). To date, OV immunotherapy has been studied in about 100 clinical trials, where a modified HSV encoding granulocyte-macrophage colony-stimulating factor, known as T-VEC, has been approved by the FDA, and another triple-mutant HSV, known as G47Δ, has been approved for the treatment of recurrent glioblastoma. It is unclear whether OV can be exploited to drive tumor cells to present TBYS cell-specific antigens, resulting in tumor cells being eradicated by TME TME TME with functional memory properties. In conclusion, the study found that OV-BYTE therapy redirected the cytotoxicity of functional TBYS cells to tumor cells to improve tumor control and had a synergistic effect with PD-L1 ICB. Therefore, the combination of OV-BYTE with PD-1 and/or PD-L1 ICB may expand the toolkit for cancer immunotherapy.
Original link https://www.nature.com/articles/s43018-024-00760-x
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