학술논문
Clonal Deletion of Tumor-Specific T Cells by Interferon-γ Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade.
Document Type
article
Author
Pai, Chien-Chun Steven; Huang, John T; Lu, Xiaoqing; Simons, Donald M; Park, Chanhyuk; Chang, Anthony; Tamaki, Whitney; Liu, Eric; Roybal, Kole T; Seagal, Jane; Chen, Mingyi; Hagihara, Katsunobu; Wei, Xiao X; DuPage, Michel; Kwek, Serena S; Oh, David Y; Daud, Adil; Tsai, Katy K; Wu, Clint; Zhang, Li; Fasso, Marcella; Sachidanandam, Ravi; Jayaprakash, Anitha; Lin, Ingrid; Casbon, Amy-Jo; Kinsbury, Gillian A; Fong, Lawrence
Source
Immunity. 50(2)
Subject
Language
Abstract
Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.