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

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 ZhangMarcella Fasso, Ravi Sachidanandam, Anitha Jayaprakash, Ingrid Lin, Amy Jo Casbon, Gillian A. Kinsbury, Lawrence Fong

Research output: Contribution to journalArticlepeer-review

82 Scopus citations


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. Although immune checkpoint blockades are being combined to enhance anti-tumor efficacy, Pai et al. find that this approach can lead to therapy resistance in the low tumor burden setting. Potent immunotherapy in this setting overdrives tumor-reactive T cells, leading to their death. Optimal immunotherapy could therefore be disease-context dependent.

Original languageEnglish
Pages (from-to)477-492.e8
Issue number2
StatePublished - 19 Feb 2019
Externally publishedYes


  • IFN-γ
  • activation-induced cell death
  • anti-CTLA-4
  • anti-PD-1
  • cancer
  • immunotherapy


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