Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy

Abstract

The immunosuppressive tumor microenvironment limits the success of current immunotherapies. The host retains memory T cells specific for previous infections throughout the entire body that are capable of executing potent and immediate immunostimulatory functions. Here we show that virus-specific memory T cells extend their surveillance to mouse and human tumors. Reactivating these antiviral T cells can arrest growth of checkpoint blockade-resistant and poorly immunogenic tumors in mice after injecting adjuvant-free non-replicating viral peptides into tumors. Peptide mimics a viral reinfection event to memory CD8+ T cells, triggering antigen presentation and cytotoxic pathways within the tumor, activating dendritic cells and natural killer cells, and recruiting the adaptive immune system. Viral peptide treatment of ex vivo human tumors recapitulates immune activation gene expression profiles observed in mice. Lastly, peptide therapy renders resistant mouse tumors susceptible to PD-L1 blockade. Thus, re-stimulating known antiviral immunity may provide a unique therapeutic approach for cancer immunotherapy.

Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer

“…Studies have reported that pathogen-specific (e.g., cytomegalovirus [ significant fraction of intratumoral CD8 + T cells (48)(49)(50)(51)(52). The impact of such antiviral immune responders on antitumor immunity demands further investigation and may have important implications for the use of MBCTs in the clinic.…”

“…Interestingly, patients whose tumors harbor the tetrapeptide, ESSA, a sequence shared by CMV, have been shown to exhibit increased survival in the context of CTLA-4 blockade (53). Further, recently in mouse models, virus-specific memory T cells have been shown to halt tumor growth when their cognate antigens are injected within the tumor to create an immune-"alarming" effect (49). In contrast to this strategy, which requires previous immunity against a specific pathogen, our work suggests that pathogenrelated therapies can be harnessed for antitumor immune responses independent of previous exposure; as in the majority of our studies, the hosts had no previous exposure to influenza virus.…”

Accumulation of CD103+ CD8+ T cells in a cutaneous melanoma micrometastasis

“…It may represent the first step in escape from immune equilibrium, or, as seen in mouse models, it may also reflect temporary tumor growth before return to immune control and quiescence, which could have lasted for a prolonged period of time if not indefinitely. Lastly, although tumor‐associated CD103 + T RM ‐like cells are often enriched for cancer‐specific cells, a large fraction of these may be made up of virus‐specific T RM cells that were generated during previous infections . As such, these bystander cells would be unable to recognise tumor antigens, meaning that a proportion of the CD103 + T RM ‐like cells may not actively take part in antitumor immunity.…”

“…Lastly, although tumor-associated CD103 + T RM -like cells are often enriched for cancer-specific cells, 25 a large fraction of these may be made up of virus-specific T RM cells that were generated during previous infections. 26,27 As such, these bystander cells would be unable to recognise tumor antigens, meaning that a proportion of the CD103 + T RM -like cells may not actively take part in antitumor immunity. Regardless, in conjunction with recent clinical and preclinical studies, this case strongly implies a role for T RM cells in providing cancer-immune surveillance and promoting cancer-immune equilibrium in human in-transit melanoma metastases and highlights the potential of targeting T RM for future cancer immunotherapies.…”

CIMT 2019: report on the 17th Annual Meeting of the Association for Cancer Immunotherapy

“…29 Virus-specific T cells populate tumors and can also be exploited for immunotherapy by treating tumors with virus-specific peptides. 30 Moving on from single-cell mass spectrometry, Thorbald van Hall (LUMC, Leiden, the Netherlands) presented his findings on NKG2A, an inhibitory molecule on NK and T cells. Specifically, the talk started on HLA-E, a highly conserved HLA type, which presents essentially the same peptide across a wide range of mammalian species.…”