title: Interdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy.
abstract: Combination therapy with α-CTLA-4 and α-PD-1 has shown significant clinical responses in different types of cancer. However, the underlying mechanisms remain elusive. Here, combining detailed analysis of human tumour samples with preclinical tumour models, we report that concomitant blockade of CTLA-4 and PD-1 improves anti-tumour immune responses and synergistically eradicates tumour. Mechanistically, combination therapy relies on the interdependence between IL-7 and IFN-γ signalling in T cells, as lack of either pathway abrogates the immune-boosting and therapeutic effects of combination therapy. Combination treatment increases IL-7Rα expression on tumour-infiltrating T cells in an IFN-γ/IFN-γR signalling-dependent manner, which may serve as a potential biomarker for clinical trials with immune checkpoint blockade. Our data suggest that combining immune checkpoint blockade with IL-7 signalling could be an effective modality to improve immunotherapeutic efficacy. Taken together, we conclude that combination therapy potently reverses immunosuppression and eradicates tumours via an intricate interplay between IFN-γ/IFN-γR and IL-7/IL-7R pathways.
authors: Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Lewis Zhichang
authors: LZ
authors: Shi
authors: Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Tihui
authors: T
authors: Fu
authors: Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Baoxiang
authors: B
authors: Guan
authors: Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Jianfeng
authors: J
authors: Chen
authors: The Immunotherapy Platform, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Jorge M
authors: JM
authors: Blando
authors: The Immunotherapy Platform, MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: James P
authors: JP
authors: Allison
authors: Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Liangwen
authors: L
authors: Xiong
authors: Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Sumit K
authors: SK
authors: Subudhi
authors: Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Jianjun
authors: J
authors: Gao
authors: Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.|The Immunotherapy Platform, MD Anderson Cancer Center, Houston, Texas 77030, USA.|Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Padmanee
authors: P
authors: Sharma
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism*; D015851:Interleukin-7 / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000276:immunology
chemical_list: D060908:CTLA-4 Antigen; D015851:Interleukin-7; D061026:Programmed Cell Death 1 Receptor; D020395:Receptors, Interleukin-7; D007371:Interferon-gamma