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Clonal Deletion of Tumor-Specific T Cells by Interferon-γ Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade.

Immunity (2019-02-10)
Chien-Chun Steven Pai, John T Huang, Xiaoqing Lu, Donald M Simons, Chanhyuk Park, Anthony Chang, Whitney Tamaki, Eric Liu, Kole T Roybal, Jane Seagal, Mingyi Chen, Katsunobu Hagihara, Xiao X Wei, Michel DuPage, Serena S Kwek, David Y Oh, Adil Daud, Katy K Tsai, Clint Wu, Li Zhang, Marcella Fasso, Ravi Sachidanandam, Anitha Jayaprakash, Ingrid Lin, Amy-Jo Casbon, Gillian A Kinsbury, Lawrence Fong
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.

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