Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy
Background Current immunotherapies still have limited successful rates among cancers. It is now recognized that T cell functional state in the tumor microenvironment (TME) is a key determinant for effective antitumor immunity and immunotherapy. In addition to exhaustion, cellular senescence in tumor...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2022-10-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/10/e005020.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823857063837564928 |
|---|---|
| author | Xia Liu Emily Shaw Fusheng Si Guangyong Peng Yan Tao Feiya Ma David Bagley Yuanqin Zhang |
| author_facet | Xia Liu Emily Shaw Fusheng Si Guangyong Peng Yan Tao Feiya Ma David Bagley Yuanqin Zhang |
| author_sort | Xia Liu |
| collection | DOAJ |
| description | Background Current immunotherapies still have limited successful rates among cancers. It is now recognized that T cell functional state in the tumor microenvironment (TME) is a key determinant for effective antitumor immunity and immunotherapy. In addition to exhaustion, cellular senescence in tumor-infiltrating T cells (TILs) has recently been identified as an important T cell dysfunctional state induced by various malignant tumors. Therefore, a better understanding of the molecular mechanism responsible for T cell senescence in the TME and development of novel strategies to prevent effector T cell senescence are urgently needed for cancer immunotherapy.Methods Senescent T cell populations in the TMEs in mouse lung cancer, breast cancer, and melanoma tumor models were evaluated. Furthermore, T cell senescence induced by mouse tumor and regulatory T (Treg) cells in vitro was determined with multiple markers and assays, including real-time PCR, flow cytometry, and histochemistry staining. Loss-of-function strategies with pharmacological inhibitors and the knockout mouse model were used to identify the potential molecules and pathways involved in T cell senescence. In addition, melanoma mouse tumor immunotherapy models were performed to explore the synergistical efficacy of antitumor immunity via prevention of tumor-specific T cell senescence combined with anti-programmed death-ligand 1 (anti-PD-L1) checkpoint blockade therapy.Results We report that both mouse malignant tumor cells and Treg cells can induce responder T cell senescence, similar as shown in human Treg and tumor cells. Accumulated senescent T cells also exist in the TME in tumor models of lung cancer, breast cancer and melanoma. Induction of ataxia-telangiectasia mutated protein (ATM)-associated DNA damage is the cause for T cell senescence induced by both mouse tumor cells and Treg cells, which is also regulated by mitogen-activated protein kinase (MAPK) signaling. Furthermore, blockages of ATM-associated DNA damage and/or MAPK signaling pathways in T cells can prevent T cell senescence mediated by tumor cells and Treg cells in vitro and enhance antitumor immunity and immunotherapy in vivo in adoptive transfer T cell therapy melanoma models. Importantly, prevention of tumor-specific T cell senescence via ATM and/or MAPK signaling inhibition combined with anti-PD-L1 checkpoint blockade can synergistically enhance antitumor immunity and immunotherapy in vivo.Conclusions These studies prove the novel concept that targeting both effector T cell senescence and exhaustion is an effective strategy and can synergistically enhance cancer immunotherapy. |
| format | Article |
| id | doaj-art-69bae1df62f44310b6adc975d60860be |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-69bae1df62f44310b6adc975d60860be2025-02-12T00:20:16ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-10-01101010.1136/jitc-2022-005020Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapyXia Liu0Emily Shaw1Fusheng Si2Guangyong Peng3Yan Tao4Feiya Ma5David Bagley6Yuanqin Zhang73 Chinese Preventive Medicine Association, Beijing, ChinaDepartment of Pathology, Southampton University Hospitals National Health Service Trust, Southampton, UKDivision of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, Missouri, USASiteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri, USADivision of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, Missouri, USADivision of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, USADepartment of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St Louis, Missouri, USABackground Current immunotherapies still have limited successful rates among cancers. It is now recognized that T cell functional state in the tumor microenvironment (TME) is a key determinant for effective antitumor immunity and immunotherapy. In addition to exhaustion, cellular senescence in tumor-infiltrating T cells (TILs) has recently been identified as an important T cell dysfunctional state induced by various malignant tumors. Therefore, a better understanding of the molecular mechanism responsible for T cell senescence in the TME and development of novel strategies to prevent effector T cell senescence are urgently needed for cancer immunotherapy.Methods Senescent T cell populations in the TMEs in mouse lung cancer, breast cancer, and melanoma tumor models were evaluated. Furthermore, T cell senescence induced by mouse tumor and regulatory T (Treg) cells in vitro was determined with multiple markers and assays, including real-time PCR, flow cytometry, and histochemistry staining. Loss-of-function strategies with pharmacological inhibitors and the knockout mouse model were used to identify the potential molecules and pathways involved in T cell senescence. In addition, melanoma mouse tumor immunotherapy models were performed to explore the synergistical efficacy of antitumor immunity via prevention of tumor-specific T cell senescence combined with anti-programmed death-ligand 1 (anti-PD-L1) checkpoint blockade therapy.Results We report that both mouse malignant tumor cells and Treg cells can induce responder T cell senescence, similar as shown in human Treg and tumor cells. Accumulated senescent T cells also exist in the TME in tumor models of lung cancer, breast cancer and melanoma. Induction of ataxia-telangiectasia mutated protein (ATM)-associated DNA damage is the cause for T cell senescence induced by both mouse tumor cells and Treg cells, which is also regulated by mitogen-activated protein kinase (MAPK) signaling. Furthermore, blockages of ATM-associated DNA damage and/or MAPK signaling pathways in T cells can prevent T cell senescence mediated by tumor cells and Treg cells in vitro and enhance antitumor immunity and immunotherapy in vivo in adoptive transfer T cell therapy melanoma models. Importantly, prevention of tumor-specific T cell senescence via ATM and/or MAPK signaling inhibition combined with anti-PD-L1 checkpoint blockade can synergistically enhance antitumor immunity and immunotherapy in vivo.Conclusions These studies prove the novel concept that targeting both effector T cell senescence and exhaustion is an effective strategy and can synergistically enhance cancer immunotherapy.https://jitc.bmj.com/content/10/10/e005020.full |
| spellingShingle | Xia Liu Emily Shaw Fusheng Si Guangyong Peng Yan Tao Feiya Ma David Bagley Yuanqin Zhang Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy Journal for ImmunoTherapy of Cancer |
| title | Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy |
| title_full | Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy |
| title_fullStr | Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy |
| title_full_unstemmed | Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy |
| title_short | Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy |
| title_sort | blockades of effector t cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy |
| url | https://jitc.bmj.com/content/10/10/e005020.full |
| work_keys_str_mv | AT xialiu blockadesofeffectortcellsenescenceandexhaustionsynergisticallyenhanceantitumorimmunityandimmunotherapy AT emilyshaw blockadesofeffectortcellsenescenceandexhaustionsynergisticallyenhanceantitumorimmunityandimmunotherapy AT fushengsi blockadesofeffectortcellsenescenceandexhaustionsynergisticallyenhanceantitumorimmunityandimmunotherapy AT guangyongpeng blockadesofeffectortcellsenescenceandexhaustionsynergisticallyenhanceantitumorimmunityandimmunotherapy AT yantao blockadesofeffectortcellsenescenceandexhaustionsynergisticallyenhanceantitumorimmunityandimmunotherapy AT feiyama blockadesofeffectortcellsenescenceandexhaustionsynergisticallyenhanceantitumorimmunityandimmunotherapy AT davidbagley blockadesofeffectortcellsenescenceandexhaustionsynergisticallyenhanceantitumorimmunityandimmunotherapy AT yuanqinzhang blockadesofeffectortcellsenescenceandexhaustionsynergisticallyenhanceantitumorimmunityandimmunotherapy |