Choi and Wang et al. showed that expression of the Epstein–Barr virus signaling protein LMP1 in B cells stimulated T cell responses to multiple tumor-associated antigens (TAAs) by upregulating several known TAAs, increasing TAAs presentation on MHC II, and upregulating costimulatory ligands. CD4+ T cells co-cultured with LMP1-expressing B cells showed increased proliferation, EOMES expression, and cytotoxicity (CD4 CTLs). Adoptive transfer of CD4 CTLs to A20 tumor-bearing mice inhibited tumor growth, and its combination with anti-PD-1 further improved survival. CD4+ T cells stimulated with LMP1-transfected autologous CLL cells showed activation and expansion into CD4 CTLs.
Contributed by Shishir Pant
ABSTRACT: Tumour-associated antigens (TAAs) comprise a large set of non-mutated cellular antigens recognized by T cells in human and murine cancers. Their potential as targets for immunotherapy has been explored for more than two decades(1), yet the origins of TAA-specific T cells remain unclear. While tumour cells may be an important source of TAAs for T cell priming(2), several recent studies suggest that infection with some viruses, including Epstein-Barr virus and influenza virus can elicit T cell responses against abnormally expressed cellular antigens that function as TAAs(3,4). However, the cellular and molecular basis of such responses remains undefined. Here we show that expression of the Epstein-Barr virus signalling protein LMP1 in B cells provokes T cell responses to multiple TAAs. LMP1 signalling leads to overexpression of many cellular antigens previously shown to be TAAs, their presentation on major histocompatibility complex classes I (MHC-I) and II (MHC-II) (mainly through the endogenous pathway) and the upregulation of costimulatory ligands CD70 and OX40L, thereby inducing potent cytotoxic CD4(+) and CD8(+) T cell responses. These findings delineate a mechanism of infection-induced anti-tumour immunity. Furthermore, by ectopically expressing LMP1 in tumour B cells from patients with cancer and thereby enabling them to prime T cells, we develop a general approach for rapid production of autologous cytotoxic CD4(+) T cells against a wide range of endogenous tumour antigens, such as TAAs and neoantigens, for treating B cell malignancies. This work stresses the need to revisit classical concepts concerning viral and tumour immunity, which will be critical to fully understand the impact of common infections on human health and to improve the rational design of immune approaches to treatment of cancers.
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncolo
Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston, MA, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Diagnostics, School of Medicine, Hangzhou Normal University, Hangzhou, China. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, China. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. School of Medicine, University of California, San Francisco, San Francisco, CA, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (7) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (8) Clinical Laboratory Division, Brigham and Women's Hospital, Boston, MA, USA. (9) Department of Medicine, Harvard Medical School, Boston, MA, USA. Clinical Laboratory Division, Brigham and Women's Hospital, Boston, MA, USA. (10) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (11) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (12) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (13) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston, MA, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston, MA, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Baochun_Zhang@dfci.harvard.edu. Department of Medicine, Harvard Medical School, Boston, MA, USA. Baochun_Zhang@dfci.harvard.edu. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Baochun_Zhang@dfci.harvard.edu.
