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Clonal Deletion of Tumor-Specific T Cells by Interferon-γ Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade
- Source :
- Immunity, vol 50, iss 2
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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 Tcells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive Tcells. Combination treatment induced deletion of tumor-specific Tcells and altered the Tcell repertoire landscape, skewing the distribution of Tcells 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.
- Subjects :
- Male
0301 basic medicine
T-Lymphocytes
Programmed Cell Death 1 Receptor
Drug Resistance
Inbred C57BL
activation-induced cell death
Mice
0302 clinical medicine
Neoplasms
Monoclonal
Immunology and Allergy
CTLA-4 Antigen
Receptor
IFN-γ
Mice, Knockout
Tumor
Melanoma
Antibodies, Monoclonal
Tumor Burden
Infectious Diseases
5.1 Pharmaceuticals
030220 oncology & carcinogenesis
immunotherapy
Immunotherapy
Development of treatments and therapeutic interventions
Combination therapy
Cell Survival
Knockout
Immunology
Clonal Deletion
Biology
Antibodies
Article
Clonal deletion
Cell Line
Vaccine Related
Experimental
Interferon-gamma
03 medical and health sciences
Immunity
Cell Line, Tumor
medicine
Animals
cancer
Humans
Inflammatory and immune system
Neoplasms, Experimental
medicine.disease
Immune checkpoint
Blockade
Mice, Inbred C57BL
030104 developmental biology
Drug Resistance, Neoplasm
Apoptosis
anti-CTLA-4
Cancer research
Neoplasm
anti-PD-1
Immunization
Subjects
Details
- ISSN :
- 10747613
- Volume :
- 50
- Database :
- OpenAIRE
- Journal :
- Immunity
- Accession number :
- edsair.doi.dedup.....873c868785fb617149aa8148605a0083