Immunity
Volume 50, Issue 2, 19 February 2019, Pages 477-492.e8
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Article
Clonal Deletion of Tumor-Specific T Cells by Interferon-γ Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade

https://doi.org/10.1016/j.immuni.2019.01.006Get rights and content
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Highlights

  • Combination checkpoint blockade leads to impaired efficacy with low tumor burden

  • This impairment results from IFN-γ-mediated deletion of tumor-reactive T cells

  • AICD is an immune-intrinsic mechanism of therapeutic resistance to checkpoint blockade

Summary

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.

Keywords

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

Cited by (0)

6

Present address: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

7

Present address: Genentech, 1 DNA Way, South San Francisco, CA 94080, USA

8

Present address: Amgen, 1120 Veterans Boulevard, South San Francisco, CA 94080, USA

9

Present address: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA

10

Lead Contact