Depletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab

AbstractRegulatory T (Treg) cells are important negative regulators of immune homeostasis, but in cancers they tone down the anti-tumor immune response. They are distinguished by high expression levels of the chemokine receptor CCR4, hence their targeting by the anti-CCR4 monoclonal antibody mogamulizumab holds therapeutic promise. Here we show that despite a significant reduction in peripheral effector Treg cells, clinical responses are minimal in a cohort of patients with advanced CCR4-negative solid cancer in a phase Ib study (NCT01929486). Comprehensive immune-monitoring reveals that the abundance of CCR4-expressing central memory CD8+ T cells that are known to play roles in the antitumor immune response is reduced. In long survivors, characterised by lower CCR4 expression in their central memory CD8+ T cells possessed and/or NK cells with an exhausted phenotype, cell numbers are eventually maintained. Our study thus shows that mogamulizumab doses that are currently administered to patients in clinical studies may not differentiate between targeting effector Treg cells and central memory CD8+ T cells, and dosage refinement might be necessary to avoid depletion of effector components during immune therapy.

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Unexpected central-memory CD8+ T cell reduction hampers the antitumor efficacy of mogamulizumab (anti-CC chemokine receptor 4 mAb) treatment

10.21203/rs.3.rs-73503/v1 ◽

2020 ◽

Author(s):

Yuka Maeda ◽

Hisashi Wada ◽

Takuro Saito ◽

Daisuke Sugiyama ◽

Takuma Irie ◽

...

Keyword(s):

T Cells ◽

Cancer Immunotherapy ◽

Optimal Dose ◽

Immune Monitoring ◽

Central Memory ◽

Solid Cancer ◽

Concomitant Reduction ◽

Clinical Responses ◽

Phase 1B ◽

Chemokine Receptor 4

Abstract Developing Treg cell-targeted therapies is an important aspect in cancer immunotherapy. Here, we investigate anti-CCR4 mAb (mogamulizumab) with solid cancer patients in phase 1b clinical trial based on the predominant detection of CCR4-expressing eTreg cells in tumors. While eTreg cells in peripheral blood were significantly decreased after mogamulizumab administration in all patients, clinical responses were hardly detected. Comprehensive immune-monitoring revealed that concomitant reduction of central-memory CD8+ T cells with CCR4 expression, that reportedly play an important role in antitumor activity. This reduction was subsided in long survivors in whom central-memory CD8+ T cells possessed lower CCR4 expression and/or NK cells exhibited an exhausted phenotype. Thus, excess doses of mogamulizumab harboring enhanced antibody-dependent cellular cytotoxicity could unexpectedly deplete central-memory CD8+ T cells with CCR4 expression. We therefore need to carefully determine the optimal dose of mogamulizumab for successful clinical application as cancer immunotherapy to avoid unexpected depletion of effector components.

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Faculty Opinions recommendation of Central memory CD8+ T cells appear to have a shorter lifespan and reduced abundance as a function of HIV disease progression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1118802.575393 ◽

2008 ◽

Author(s):

Guido Silvestri

Keyword(s):

T Cells ◽

Disease Progression ◽

Cd8 T Cells ◽

Central Memory ◽

Hiv Disease ◽

Memory Cd8 T Cells

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Central memory CD8+ T cells become CD69+ tissue-residents during viral skin infection independent of CD62L-mediated lymph node surveillance

PLoS Pathogens ◽

10.1371/journal.ppat.1007633 ◽

2019 ◽

Vol 15 (3) ◽

pp. e1007633 ◽

Cited By ~ 12

Author(s):

Jossef F. Osborn ◽

Samuel J. Hobbs ◽

Jana L. Mooster ◽

Tahsin N. Khan ◽

Augustus M. Kilgore ◽

...

Keyword(s):

T Cells ◽

Lymph Node ◽

Cd8 T Cells ◽

Skin Infection ◽

Central Memory ◽

Memory Cd8 T Cells

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Immunological effect of irreversible electroporation on solid tumors

10.21203/rs.3.rs-121118/v1 ◽

2020 ◽

Author(s):

Xiaoxia Guo ◽

Fang Du ◽

Qin Liu ◽

Yan Guo ◽

Qingbing Wang ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Nk Cells ◽

Irreversible Electroporation ◽

Treg Cells ◽

T Cell Subsets ◽

Activated T Cells ◽

Immunological Effect ◽

Immunological Effects ◽

And Control

Abstract Background This study intends to investigate the immunological effects of tumor ablation with irreversible electroporation (IRE). Methods We evaluated the systemic immune response in patients with hepatocellular carcinoma (HCC) after IRE treatment. Furthermore, we analyzed the tumor infiltrating T lymphocytes and the level of serum cytokines in IRE and control groups of tumor-bearing mice. Results We observed that IRE induced an increase in WBC, neutrophil and monocyte counts and a decrease in lymphocyte count 1 day post-IRE and returned to baseline values within 7 days in the patients. Meanwhile, circulating CD4+ T cell subsets, but not CD8+, decreased 1 day post-IRE. The activated T cells and natural killer (NK) cells increased, and regulatory T (Treg) cells decreased. Furthermore, a significant increase in cytotoxic CD8+ T cells infiltration was observed on ablative tumors in mice. The level of serum IFN-γ also significantly increased in the IRE group. Conclusions Our study demonstrated that IRE not only induced immediate innate immune response dominated by the increase of neutrophils, monocytes and NK cells, but also upregulated activated T cells and downregulated Treg. Meanwhile, the results from the animal model indicated that IRE could induce antitumor adaptive immunity dominated by cytotoxic CD8+ T cells.

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Interleukin-15 Favors the Expansion of Central Memory CD8+ T Cells in Ex Vivo Generated, Antileukemia Human Cytotoxic T Lymphocyte Lines

Journal of Immunotherapy ◽

10.1097/cji.0b013e31816b1092 ◽

2008 ◽

Vol 31 (4) ◽

pp. 385-393 ◽

Cited By ~ 16

Author(s):

Liane Daudt ◽

Rita Maccario ◽

Franco Locatelli ◽

Ilaria Turin ◽

Lucia Silla ◽

...

Keyword(s):

T Cells ◽

T Lymphocyte ◽

Cd8 T Cells ◽

Cytotoxic T Lymphocyte ◽

Ex Vivo ◽

Central Memory ◽

Memory Cd8 T Cells ◽

Interleukin 15

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Prolongation of survival following depletion of CD4+CD25+ regulatory T cells in mice with experimental brain tumors

Journal of Neurosurgery ◽

10.3171/jns.2006.105.3.430 ◽

2006 ◽

Vol 105 (3) ◽

pp. 430-437 ◽

Cited By ~ 101

Author(s):

Abdeljabar El Andaloussi ◽

Yu Han ◽

Maciej S. Lesniak

Keyword(s):

Immune Response ◽

T Cells ◽

Brain Tumors ◽

Malignant Gliomas ◽

Tumor Infiltrating Lymphocytes ◽

Treg Cells ◽

Separate Experiment ◽

The Central Nervous System ◽

Novel Target ◽

Infiltrating Lymphocytes

Object Regulatory CD4+CD25+ T cells have been shown to play an important role in the regulation of the immune response. Whereas the presence of these cells has been associated with immune suppression, the lack of regulatory T (Treg) cells has been shown to induce autoimmunity. The purpose of this study was to define the role of Treg cells in tumors of the central nervous system (CNS). Methods The authors implanted syngeneic GL261 tumor cells in the brains or flanks of C57BL/6 mice. The resulting tumors were later removed at specific time points, and the presence of tumor-infiltrating lymphocytes was analyzed by performing flow cytometry for the presence of Treg cells. In a separate experiment, mice with GL261 tumors were treated with injections of anti-CD25 monoclonal antibody (mAb) to determine whether depletion of Treg cells may have an impact on the length of survival in mice with brain tumors. Tumor-infiltrating lymphocytes isolated from mice with GL261 tumors were found to have a significant increase in the presence of Treg cells compared with control lymphocytes (p < 0.05). Moreover, Treg cells isolated in murine brain tumors expressed FoxP3, CTLA-4, and CD62L. Mice treated with anti-CD25 mAb lived significantly longer than tumor-bearing control animals (p < 0.05). An analysis of brains in surviving animals showed a depletion of CD4+CD25+ T cells. Conclusions The results of this study indicate that CD4+CD25+ Treg cells play an important role in suppressing the immune response to CNS tumors. These Treg cells may therefore represent a potentially novel target for immunotherapy of malignant gliomas.

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Clinical-scale selection and viral transduction of human naïve and central memory CD8+ T cells for adoptive cell therapy of cancer patients

Cancer Immunology Immunotherapy ◽

10.1007/s00262-013-1459-x ◽

2013 ◽

Vol 62 (10) ◽

pp. 1563-1573 ◽

Cited By ~ 31

Author(s):

Anna Casati ◽

Azam Varghaei-Nahvi ◽

Steven Alexander Feldman ◽

Mario Assenmacher ◽

Steven Aaron Rosenberg ◽

...

Keyword(s):

T Cells ◽

Cell Therapy ◽

Cancer Patients ◽

Cd8 T Cells ◽

Adoptive Cell Therapy ◽

Central Memory ◽

Clinical Scale ◽

Scale Selection ◽

Memory Cd8 T Cells ◽

Viral Transduction

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Abstract 2883: Improved generation of central memory CD8+ T cells with CD40L expressing recombinant vaccinia virus

10.1158/1538-7445.am2014-2883 ◽

2014 ◽

Author(s):

Emanuele Trella ◽

Evangelos Panoupolos ◽

Swantje Heidtmann ◽

Nermin Raafat ◽

Giulio Cesare Spagnoli ◽

...

Keyword(s):

T Cells ◽

Vaccinia Virus ◽

Cd8 T Cells ◽

Recombinant Vaccinia Virus ◽

Central Memory ◽

Recombinant Vaccinia ◽

Memory Cd8 T Cells

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Relevance of Regulatory T Cells during Colorectal Cancer Development

Cancers ◽

10.3390/cancers12071888 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1888 ◽

Cited By ~ 1

Author(s):

Jonadab E. Olguín ◽

Itzel Medina-Andrade ◽

Tonathiu Rodríguez ◽

Miriam Rodríguez-Sosa ◽

Luis I. Terrazas

Keyword(s):

Colorectal Cancer ◽

Immune Response ◽

T Cells ◽

Regulatory T Cells ◽

Tumor Development ◽

Treg Cells ◽

Different Types ◽

Inflammatory Profile ◽

The Many ◽

Effector Immune Response

In recent years, there has been a significant increase in the study of own and foreign human factors favoring the development of different types of cancer, including genetic and environmental ones. However, the fact that the immune response plays a fundamental role in the development of immunity and susceptibility to colorectal cancer (CRC) is much stronger. Among the many cell populations of the immune system that participate in restricting or favoring CRC development, regulatory T cells (Treg) play a major role in orchestrating immunomodulation during CRC. In this review, we established concrete evidence supporting the fact that Treg cells have an important role in the promotion of tumor development during CRC, mediating an increasing suppressive capacity which controls the effector immune response, and generating protection for tumors. Furthermore, Treg cells go through a process called “phenotypic plasticity”, where they co-express transcription factors that promote an inflammatory profile. We reunited evidence that describes the interaction between the different effector populations of the immune response and its modulation by Treg cells adapted to the tumor microenvironment, including the mechanisms used by Treg cells to suppress the protective immune response, as well as the different subpopulations of Treg cells participating in tumor progression, generating susceptibility during CRC development. Finally, we discussed whether Treg cells might or might not be a therapeutic target for an effective reduction in the morbidity and mortality caused by CRC.

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