scholarly journals Dietary methionine restriction impairs anti-tumor immunity through gut microbiota

2021 ◽  
Author(s):  
Ming Li ◽  
Xiaojiang Xu ◽  
Qing Xu ◽  
Xin Xu ◽  
M Andrea Azcarate-Peril ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Immune System ◽  
T Cell ◽  
Gut Microbiota ◽  
Tumor Growth ◽  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cancer Growth ◽  
Methionine Restriction

Dietary methionine restriction has been reported to repress cancer growth and improve therapeutic responses in several pre-clinical settings. However, how this dietary intervention impacts cancer progression in the context of the intact immune system is unknown. Here we report that methionine restriction exacerbates cancer growth and influences the outcomes of anti-tumor immunotherapy through gut microbiota and immune suppression in immunocompetent settings. Methionine restriction reduces T cell activation, increases tumor growth, and impairs response to anti-tumor immunotherapy. Mechanistically, methionine restriction alters composition of gut microbiota and reduces microbial production of hydrogen sulfide. Fecal transplantation from methionine-restricted tumor-free animals is sufficient to repress T cell activation and enhance tumor growth in tumor-bearing recipient mice. Conversely, dietary supplementation of a hydrogen sulfide donor or methionine stimulates anti-tumor immunity and suppresses tumor progression. Our findings reveal a vital role of gut microbiota in mediating methionine restriction-induced suppression of anti-tumor immunity and suggest that any possible anti-cancer benefits of methionine restriction require careful considerations of both the microbiota and the immune system.

scholarly journals ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Youqian Wu ◽  
Chao Zhang ◽  
Xiaolan Liu ◽  
Zhengfu He ◽  
Bing Shan ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Tumor Immunity ◽  
T Cell Activation ◽  
Drug Targets ◽  
Cell Activation ◽  
Proteasomal Degradation ◽  
Cytotoxic T Cell ◽  
Immunocompromised Mice

AbstractCancer expression of PD-L1 suppresses anti-tumor immunity. PD-L1 has emerged as a remarkable therapeutic target. However, the regulation of PD-L1 degradation is not understood. Here, we identify several compounds as inducers of PD-L1 degradation using a high-throughput drug screen. We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. Overexpression of ARIH1 suppresses tumor growth and promotes cytotoxic T cell activation in wild-type, but not in immunocompromised mice, highlighting the role of ARIH1 in anti-tumor immunity. Moreover, combining EGFR inhibitor ES-072 with anti-CTLA4 immunotherapy results in an additive effect on both tumor growth and cytotoxic T cell activation. Our results delineate a mechanism of PD-L1 degradation and cancer escape from immunity via EGFR-GSK3α-ARIH1 signaling and suggest GSK3α and ARIH1 might be potential drug targets to boost anti-tumor immunity and enhance immunotherapies.

scholarly journals Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy

2021 ◽  
Vol 12 ◽  
Author(s):  
Sukanya Raghavan ◽  
Nataliya Tovbis-Shifrin ◽  
Christina Kochel ◽  
Anandi Sawant ◽  
Marielle Mello ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Tamoxifen Treatment ◽  
Phenotypic Analysis ◽  
The Impact

Programmed cell death-1 (PD-1) blockade has a profound effect on the ability of the immune system to eliminate tumors, but many questions remain about the cell types involved and the underlying mechanisms of immune activation. To shed some light on this, the cellular and molecular events following inhibition of PD-1 signaling was investigated in the MC-38 colon carcinoma model using constitutive (PD-1 KO) and conditional (PD1cKO) mice and in wild-type mice treated with PD-1 antibody. The impact on both tumor growth and the development of tumor immunity was assessed. In the PD-1cKO mice, a complete deletion of Pdcd1 in tumor-infiltrating T cells (TILs) after tamoxifen treatment led to the inhibition of tumor growth of both small and large tumors. Extensive immune phenotypic analysis of the TILs by flow and mass cytometry identified 20-different T cell subsets of which specifically 5-CD8 positive ones expanded in all three models after PD-1 blockade. All five subsets expressed granzyme B and interferon gamma (IFNγ). Gene expression analysis of the tumor further supported the phenotypic analysis in both PD-1cKO- and PD-1 Ab-treated mice and showed an upregulation of pathways related to CD4 and CD8 T-cell activation, enhanced signaling through costimulatory molecules and IFNγ, and non-T-cell processes. Altogether, using PD-1cKO mice, we define the intrinsic nature of PD-1 suppression of CD8 T-cell responses in tumor immunity.

scholarly journals DCision-making in tumors governs T cell anti-tumor immunity

Oncogene ◽  
2021 ◽  
Author(s):  
Francesca Alfei ◽  
Ping-Chih Ho ◽  
Wan-Lin Lo
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Cancer Treatment ◽  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Genetic Alterations ◽  
Immune Checkpoint Blockade ◽  
Oncological Treatment

AbstractThe exploitation of T cell-based immunotherapies and immune checkpoint blockade for cancer treatment has dramatically shifted oncological treatment paradigms and broadened the horizons of cancer immunology. Dendritic cells have emerged as the critical tailors of T cell immune responses, which initiate and coordinate anti-tumor immunity. Importantly, genetic alterations in cancer cells, cytokines and chemokines produced by cancer and stromal cells, and the process of tumor microenvironmental regulation can compromise dendritic cell–T cell cross-talk, thereby disrupting anti-tumor T cell responses. This review summarizes how T cell activation is controlled by dendritic cells and how the tumor microenvironment alters dendritic cell properties in the context of the anti-tumor immune cycle. Furthermore, we will highlight therapeutic options for tailoring dendritic cell-mediated decision-making in T cells for cancer treatment.

Abstract 220: Gut Microbiota Alterations Associate With T Cell Activation and Adverse Cardiac Remodeling in Response to Cardiac Pressure Overload

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Francisco J Carrillo-salinas ◽  
Njabulo Ngwenyama ◽  
Marina Anastasiou ◽  
Kuljeet Kaur ◽  
Mark Aronovitz ◽  
...  
Keyword(s):  
T Cell ◽  
Gut Microbiota ◽  
T Cell Activation ◽  
Cardiac Remodeling ◽  
Cell Activation ◽  
Pressure Overload

scholarly journals Agonist Anti-Human CD27 Monoclonal Antibody Induces T Cell Activation and Tumor Immunity in Human CD27–Transgenic Mice

2013 ◽  
Vol 191 (8) ◽  
pp. 4174-4183 ◽  
Author(s):  
Li-Zhen He ◽  
Naseem Prostak ◽  
Lawrence J. Thomas ◽  
Laura Vitale ◽  
Jeffrey Weidlick ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Transgenic Mice ◽  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation

Next Generation of Immunotherapy for Melanoma

2008 ◽  
Vol 26 (20) ◽  
pp. 3445-3455 ◽  
Author(s):  
John M. Kirkwood ◽  
Ahmad A. Tarhini ◽  
Monica C. Panelli ◽  
Stergios J. Moschos ◽  
Hassane M. Zarour ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
The United States ◽  
Cytotoxic Agents ◽  
Antitumor Immune Response ◽  
Phase Iii

PurposeImmunotherapy has a long history with striking but limited success in patients with melanoma. To date, interleukin-2 and interferon-alfa2b are the only approved immunotherapeutic agents for melanoma in the United States.DesignTumor evasion of host immune responses, and strategies for overcoming tumor-induced immunosuppression are reviewed. Several novel immunotherapies currently in worldwide phase III clinical testing for melanoma are discussed.ResultsThe limitations of immunotherapy for melanoma stem from tumor-induced mechanisms of immune evasion that render the host tolerant of tumor antigens. For example, melanoma inhibits the maturation of antigen-presenting cells, preventing full T-cell activation and downregulating the effector antitumor immune response. New immunotherapies targeting critical regulatory elements of the immune system may overcome tolerance and promote a more effective antitumor immune response. These include monoclonal antibodies that block the cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and toll-like receptor 9 (TLR9) agonists. Blockade of CTLA4 prevents inhibitory signals that downregulate T-cell activation. TLR9 agonists stimulate dendritic cell maturation and ultimately induce a more effective immune response. These approaches have been shown to stimulate acute immune activation with concomitant appearance of transient adverse events mediated by the immune system. The pattern and duration of immune responses associated with these new modalities differ from those associated with cytokines and cytotoxic agents. In addition, vaccines are being developed that may ultimately target melanoma either alone or in combination with these immunomodulatory therapies.ConclusionThe successes of cytokine and interferon therapy of melanoma, coupled with an array of new approaches, are generating new enthusiasm for the immunotherapy of melanoma.

scholarly journals T Helper 17 Cells Promote Cytotoxic T Cell Activation in Tumor Immunity

Immunity ◽  
2009 ◽  
Vol 31 (5) ◽  
pp. 787-798 ◽  
Author(s):  
Natalia Martin-Orozco ◽  
Pawel Muranski ◽  
Yeonseok Chung ◽  
Xuexian O. Yang ◽  
Tomohide Yamazaki ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Cell ◽  
T Helper ◽  
T Helper 17 ◽  
T Helper 17 Cells

Novel HPV-E7 immune modulators to activate HPV-specific T cells to eliminate cervical cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18027-e18027
Author(s):  
Lihua Shi ◽  
Di Zhang ◽  
Susan Tam ◽  
Man-Cheong Fung
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cell Activity ◽  
Epitope Peptide ◽  
Hpv E7

e18027 Background: Human papilloma virus (HPV) infection can lead to several types of cancers in both men and women. HPV+ tumor cells constitutively express the HPV-E7 antigen which can act as an oncogene to promote tumor growth and malignant transformation. Here, we report the application of novel Tavo Immune Modulator (TIM) biologics molecules which are consisted of a pMHC complex with an epitope peptide derived from HPV-E7 and co-stimulatory modulators of T cell activity. The HPV-E7 TIM molecules can specifically recognize and activate HPV-E7-specific T cells for the elimination of HPV affected cells. Methods: HPV-E7 TIM molecules were engineered as fusion molecules with HLA-A*02:01 MHC complexed with an HPV-E7 (11-20) epitope peptide at the N-termini, and various T cell costimulatory modulators at the C-termini of IgG heavy and light chains. TIM molecules were expressed in Expi293 cells and purified by Protein A affinity chromatography. Specific binding of TIM with HPV-E7 specific T cells was confirmed by immunostaining and flow cytometry. The activation and expansion of antigen specific CD8+ T cells were elucidated in T cell activation and recall assays. Results: HPV-E7 TIM molecules with various T cell co-stimulator molecules were engineered to specifically recognize HPV-specific T cells. Activation of T cells was antigen-specific and depended on the presence of an engineered T cell modulatory component on the TIM framework. The effects of various costimulatory molecules in different combinations on T cell activation were explored and an optimal combination was identified which facilitated high potency antigen-specific T cell activation. Such molecular combinations could facilitate T cell expansion and activation in T cell recall assays. Efficacy of HPV-E7 TIM molecules by inhibiting tumor growth in a syngeneic tumor model is ongoing. Conclusions: This study demonstrates that HPV-E7 TIM molecules selectively recognize and activate HPV-specific CD8+ T cells in the presence of a combination of two T cell costimulatory factors. Such novel biologics provide distinctive approaches in the treatment of HPV-related cancers and warrant further investigation. Additional in vitro and in vivo studies are ongoing to demonstrate the utility in eliminating HPV-infected tumor cells. Full data will be presented at the meeting.

scholarly journals Hydrogen Sulfide Is an Endogenous Potentiator of T Cell Activation

2011 ◽  
Vol 287 (6) ◽  
pp. 4211-4221 ◽  
Author(s):  
Thomas W. Miller ◽  
Evelyn A. Wang ◽  
Serge Gould ◽  
Erica V. Stein ◽  
Sukhbir Kaur ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation

scholarly journals Engineering T-Cell Activation for Immunotherapy by Mechanical Forces

2021 ◽  
pp. 553-591
Author(s):  
Elena Locci ◽  
Silvia Raymond
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Cells ◽  
Cancer Therapies ◽  
Physical Barriers ◽  
Keywords Cancer ◽  
New Cancer Therapies

A groundbreaking study led by engineering and medical researchers at the California South University (CSU) shows how immune cells engineered in new cancer therapies can overcome physical barriers so that the patient's own immune system can fight tumors. This research could improve the future of millions of cancer patients worldwide. Immunotherapy, instead of using chemicals or radiation, is a type of cancer treatment that helps the patient's immune system fight cancer. T cells are a type of white blood cell that is essential for the body's immune system. Cytotoxic T cells are like soldiers searching for and destroying target invading cells. Although there has been success in using immunotherapy for some types of cancer in the blood or blood-producing organs, T cell work is much more difficult in solid tumors. Keywords: Cancer; Cells; Tissues, Tumors; Prevention, Prognosis; Diagnosis; Imaging; Screening; Treatment; Management

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