Using a combination of traceable neoantigen-encoding, fluorescently tagged lentiviruses to induce sarcomagenesis following i.m. injection in GEM mice, tamoxifen-inducible neoantigen deletion, and patience to follow mouse models for many months, Cheung and Hunt et al. took on the problem of understanding immunoediting early after tumor initiation. Multi-clonal initiating events led to the presence of antigen-negative subclones, even in the absence of T cell editing, and the ability (or lack thereof) of neoantigen-targeting T cells to eliminate antigen-negative bystander cells through an IFNγ-dependent mechanism early (day 5-10 during the peak initial T cell response) after sarcomagenesis determined escape or elimination.
Contributed by Ed Fritsch
ABSTRACT: T cells edit tumors by eliminating neoantigen-expressing tumor cells. Yet, how and when this is achieved remains uncertain. Using a murine sarcoma model with fluorescent neoantigens, we found that tumors developed later and in fewer T cell-sufficient mice (_53% penetrance) than T cell-deficient mice (_100%). With T cells, all emergent tumor cells had silenced neoantigens, but neoantigen-negative tumor cells were also present in every T cell-deficient mouse. This suggested silencing was necessary but not sufficient for outgrowth. Genetic removal of neoantigens restored tumor penetrance if implemented on day 5 post-tumor initiation, but not day 10, because CD8(+) and CD4(+) T cells infiltrated the tissue and eliminated most neoantigen-positive and -negative tumor cells within 8 days. Single-cell analyses on day-7 tumors showed oncogenic changes including increased proliferation and T cell-dependent upregulation of the IFN_-response gene Cd274 (PD-L1). T cell-depletion rescued both neoantigen-positive and -negative cells, while IFN_ blockade rescued only negative cells. This shows that T cells efficiently edit sarcomas of neoantigens and prevent early tumors via IFN_-independent and IFN_-dependent (bystander) mechanisms.
Author Info: (1) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (2) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (3
Author Info: (1) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (2) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (3) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (4) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (5) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (6) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (7) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (8) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (9) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (10) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (11) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (12) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (13) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (14) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (15) Department of Biostatistics, Yale University, New Haven, CT, USA. (16) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (17) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (18) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Electronic address: nikhil.joshi@yale.edu.
