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      T‐cell modulation by cyclophosphamide for tumour therapy

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          Summary

          The power of T cells for cancer treatment has been demonstrated by the success of co‐inhibitory receptor blockade and adoptive T‐cell immunotherapies. These treatments are highly successful for certain cancers, but are often personalized, expensive and associated with harmful side effects. Other T‐cell‐modulating drugs may provide additional means of improving immune responses to tumours without these disadvantages. Conventional chemotherapeutic drugs are traditionally used to target cancers directly; however, it is clear that some also have significant immune‐modulating effects that can be harnessed to target tumours. Cyclophosphamide is one such drug; used at lower doses than in mainstream chemotherapy, it can perturb immune homeostasis, tipping the balance towards generation of anti‐tumour T‐cell responses and control of cancer growth. This review discusses its growing reputation as an immune‐modulator whose multiple effects synergize with the microbiota to tip the balance towards tumour immunity offering widespread benefits as a safe, and relatively inexpensive component of cancer immunotherapy.

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          Most cited references65

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          Regulatory T cells in cancer immunotherapy

          FOXP3-expressing regulatory T (Treg) cells, which suppress aberrant immune response against self-antigens, also suppress anti-tumor immune response. Infiltration of a large number of Treg cells into tumor tissues is often associated with poor prognosis. There is accumulating evidence that the removal of Treg cells is able to evoke and enhance anti-tumor immune response. However, systemic depletion of Treg cells may concurrently elicit deleterious autoimmunity. One strategy for evoking effective tumor immunity without autoimmunity is to specifically target terminally differentiated effector Treg cells rather than all FOXP3+ T cells, because effector Treg cells are the predominant cell type in tumor tissues. Various cell surface molecules, including chemokine receptors such as CCR4, that are specifically expressed by effector Treg cells can be the candidates for depleting effector Treg cells by specific cell-depleting monoclonal antibodies. In addition, other immunological characteristics of effector Treg cells, such as their high expression of CTLA-4, active proliferation, and apoptosis-prone tendency, can be exploited to control specifically their functions. For example, anti-CTLA-4 antibody may kill effector Treg cells or attenuate their suppressive activity. It is hoped that combination of Treg-cell targeting (e.g., by reducing Treg cells or attenuating their suppressive activity in tumor tissues) with the activation of tumor-specific effector T cells (e.g., by cancer vaccine or immune checkpoint blockade) will make the current cancer immunotherapy more effective.
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            Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy.

            Checkpoint blockade immunotherapies can be extraordinarily effective, but might benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when appropriately selected immunogenic drugs (e.g., oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53) were used. The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8(+) T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs.
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              Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.

              CD4+CD25+ regulatory T cells are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that one injection of cyclophosphamide could significantly decrease both numbers and suppressive functions of regulatory T cells, facilitating vaccine-induced tumor rejection. In humans, iterative low dosing of cyclophosphamide, referred to as "metronomic" therapy, has recently been used in patients with advanced chemotherapy resistant cancers with the aim of reducing tumor angiogenesis. Here we show that oral administration of metronomic cyclophosphamide in advanced cancer patients induces a profound and selective reduction of circulating regulatory T cells, associated with a suppression of their inhibitory functions on conventional T cells and NK cells leading to a restoration of peripheral T cell proliferation and innate killing activities. Therefore, metronomic regimen of cyclophosphamide does not only affect tumor angiogenesis but also strongly curtails immunosuppressive regulatory T cells, favoring a better control of tumor progression. Altogether these data support cyclophosphamide regimen as a valuable treatment for reducing tumor-induced immune tolerance before setting to work anticancer immunotherapy.
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                Author and article information

                Contributors
                gallimoream@cardiff.ac.uk
                Journal
                Immunology
                Immunology
                10.1111/(ISSN)1365-2567
                IMM
                Immunology
                John Wiley and Sons Inc. (Hoboken )
                0019-2805
                1365-2567
                09 March 2018
                May 2018
                09 March 2018
                : 154
                : 1 ( doiID: 10.1111/imm.2018.154.issue-1 )
                : 62-68
                Affiliations
                [ 1 ] Division of Infection & Immunity School of Medicine Cardiff University Cardiff UK
                [ 2 ]Present address: Faculty of Medicine Nursing and Health Sciences School of Biomedical Sciences Monash University Melbourne Australia
                Author notes
                [*] [* ] Correspondence: Awen Gallimore, Division of Infection & Immunity, School of Medicine, Cardiff University, Henry Wellcome BuildingHeath Park, Cardiff CF119HP, UK. Email: gallimoream@ 123456cardiff.ac.uk

                Senior author: Awen Gallimore

                Author information
                http://orcid.org/0000-0001-6675-7004
                Article
                IMM12913
                10.1111/imm.12913
                5904691
                29460448
                2aeeae8a-0b9e-4d0f-a479-63f5c754da6a
                © 2018 The Authors. Immunology Published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 December 2017
                : 13 February 2018
                : 14 February 2018
                Page count
                Figures: 1, Tables: 0, Pages: 7, Words: 6376
                Funding
                Funded by: Cancer Research UK
                Award ID: C16731/A21200
                Funded by: Tenovus
                Award ID: 2013/L22
                Funded by: Cancer Research Wales
                Award ID: 5272BR
                Funded by: Cardiff University Systems Immunity Research Institute
                Categories
                Review Article
                Review Articles
                Custom metadata
                2.0
                imm12913
                May 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:18.04.2018

                Immunology
                cancer,cyclophosphamide,regulatory t cells,t cells
                Immunology
                cancer, cyclophosphamide, regulatory t cells, t cells

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