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      Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis

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          Abstract

          Patients with cancer with liver metastasis demonstrate significantly worse outcomes than those without liver metastasis when treated with anti–PD-1 immunotherapy. The mechanism of liver metastases–induced reduction in systemic antitumor immunity is unclear. Using a dual-tumor immunocompetent mouse model, we found that the immune response to tumor antigen presence within the liver led to the systemic suppression of antitumor immunity. The immune suppression was antigen specific and associated with the coordinated activation of regulatory T cells (Tregs) and modulation of intratumoral CD11b+ monocytes. The dysfunctional immune state could not be reversed by anti–PD-1 monotherapy unless Treg cells were depleted (anti–CTLA-4) or destabilized (EZH2 inhibitor). Thus, this study provides a mechanistic understanding and rationale for adding Treg and CD11b+ monocyte targeting agents in combination with anti–PD-1 to treat patients with cancer with liver metastasis.

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          Most cited references43

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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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            PD-1 + regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer

            Significance PD-1 blockade is a cancer immunotherapy effective in various types of cancer. However, we observed rapid cancer progression, called hyperprogressive disease (HPD), in ∼10% of advanced gastric cancer patients treated with anti–PD-1 monoclonal antibody. Tumors of HPD patients possessed highly proliferating FoxP3+ Treg cells after treatment, contrasting with their reduction in non-HPD tumors. In vitro PD-1 blockade augmented proliferation and suppressive activity of human Treg cells. Likewise, murine Treg cells that were deficient in PD-1 signaling were more proliferative and immunosuppressive. Thus, HPD may occur when PD-1 blockade activates and expands tumor-infiltrating PD-1+ Treg cells to overwhelm tumor-reactive PD-1+ effector T cells. Depletion of the former may therefore help treat and prevent HPD.
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              Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells.

              Antitumor activity of CTLA-4 antibody blockade is thought to be mediated by interfering with the negative regulation of T-effector cell (Teff) function resulting from CTLA-4 engagement by B7-ligands. In addition, a role for CTLA-4 on regulatory T cells (Treg), wherein CTLA-4 loss or inhibition results in reduced Treg function, may also contribute to antitumor responses by anti-CTLA-4 treatment. We have examined the role of the immunoglobulin constant region on the antitumor activity of anti-CTLA-4 to analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies. Anti-CTLA-4 antibody containing the murine immunoglobulin G (IgG)2a constant region exhibits enhanced antitumor activity in subcutaneous established MC38 and CT26 colon adenocarcinoma tumor models compared with anti-CTLA-4 containing the IgG2b constant region. Interestingly, anti-CTLA-4 antibodies containing mouse IgG1 or a mutated mouse IgG1-D265A, which eliminates binding to all Fcγ receptors (FcγR), do not show antitumor activity in these models. Assessment of Teff and Treg populations at the tumor and in the periphery showed that anti-CTLA-4-IgG2a mediated a rapid and dramatic reduction of Tregs at the tumor site, whereas treatment with each of the isotypes expanded Tregs in the periphery. Expansion of CD8(+) Teffs is observed with both the IgG2a and IgG2b anti-CTLA-4 isotypes, resulting in a superior Teff to Treg ratio for the IgG2a isotype. These data suggest that anti-CTLA-4 promotes antitumor activity by a selective reduction of intratumoral Tregs along with concomitant activation of Teffs. ©2013 AACR.
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                Author and article information

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                Journal
                Science Immunology
                Sci. Immunol.
                American Association for the Advancement of Science (AAAS)
                2470-9468
                October 02 2020
                October 02 2020
                October 02 2020
                October 02 2020
                : 5
                : 52
                : eaba0759
                Affiliations
                [1 ]Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
                [2 ]Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA.
                [3 ]Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
                [4 ]Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
                [5 ]QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
                [6 ]Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA.
                [7 ]Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.
                [8 ]Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA.
                Article
                10.1126/sciimmunol.aba0759
                7755924
                33008914
                4a608cdc-f706-4e06-b659-2004d63868f4
                © 2020

                https://www.sciencemag.org/about/science-licenses-journal-article-reuse

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