Horton et al. found that tumor-infiltrating PD-1+LAG-3+4-1BB+ CD8+ lymphocytes (TILs) within progressing tumors were stuck in a vicious cycle of antigen-stimulated proliferation and enhanced apoptosis (possibly due to high levels of DNA damage), leading to limited accumulation and poor tumor control. Preventing apoptosis by either overexpression of the anti-apoptotic molecule Bcl-xL or combination of agonist 4-1BB antibody with a blockade of either CTLA-4 or PD-L1 led to increased CD8+ TIL accumulation and improved tumor control.
Subsets of human tumors are infiltrated with tumor antigen-specific CD8+ T cells (TILs) despite tumor progression. These TILs are thought to be inactivated by the immunosuppressive tumor microenvironment, through the engagement of inhibitory receptors such as CTLA-4 and PD-1. However, antigen-specific CD8+ TILs are not functionally inert, but are undergoing activation in situ. Here, we show that antigen-specific CD8+ TIL are actively proliferating, yet also undergo high rates of apoptosis, leading to a vicious cycle of activation and death that limits immune efficacy. Preventing CD8+ TIL apoptosis by Bcl-xL overexpression enabled accumulation and improved tumor control. Effective combination immunotherapy with an agonist 4-1BB monoclonal antibody plus either CTLA-4 or PD-L1 neutralization led to a marked accumulation of specific CD8+ TILs through decreased apoptosis rather than increased T-cell entry or proliferation. Our data suggest that antigen-driven apoptosis of CD8+ TILs is a barrier to effective spontaneous antitumor immunity and should be considered as a critical factor in the development of cancer immunotherapies.
Author Info: (1) Department of Pathology, Section of Hematology/Oncology, the University of Chicago. (2) Department of Pathology, Section of Hematology/Oncology, the University of Chicago. (3)
Author Info: (1) Department of Pathology, Section of Hematology/Oncology, the University of Chicago. (2) Department of Pathology, Section of Hematology/Oncology, the University of Chicago. (3) The Committee on Immunology, the University of Chicago. (4) Department of Pathology, Section of Hematology/Oncology, the University of Chicago. (5) Department of Medicine, Section of Hematology/Oncology, the University of Chicago tgajewsk@medicine.bsd.uchicago.edu.
