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      Lithraea caustic (Litre) Extract Promotes an Antitumor Response Against B16 Melanoma

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          Abstract

          Melanoma immunotherapy, specifically the autotransplant of dendritic cells charged with tumors antigens, has shown promising results in clinical trials. The positive clinical effects of this therapy have been associated to increased Th17 response and delayed-type hypersensitivity (DTH) against to tumor antigens. Some synthetic compounds, such as diphenylcyclopropenone (DPCP), are capable of triggering a DTH response in cutaneous malignancies and also to induce clinically relevant effects against melanoma. In this work, we evaluated Litre extract (LExT), a standardized extract of a Chilean stinging plant, Lithraea caustic (Litre). As Litre plant is known to induce DTH, we used a murine B16 melanoma model to compare the topical and intratumor efficacy of LExT with synthetic DTH inducers (DPCP and 2,4-dinitrochlorobenzene [DNCB]). LExt contained mainly long chain catechols and sesquiterpenes. The intratumor injection of LExT induced a significant delay in tumor growth, similarly topical treatment of an established tumor with 0.1% LExT ointment induced a growth delay and even tumor regression in 15% of treated animals. No significant changes were observed on the T-cell populations associated to LExT treatment, and neither DNCB nor DPCP were capable to induce none of the LExT-induced antitumoral effects. Interestingly, our results indicate that LExT induces an antitumor response against melanoma in a mouse model and could bring a new –and affordable- treatment for melanoma in humans.

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          PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.

          Vaccination with irradiated B16 melanoma cells expressing either GM-CSF (Gvax) or Flt3-ligand (Fvax) combined with antibody blockade of the negative T-cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding alphaPD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-myeloid-derived suppressor cell ratios within B16 melanomas. IFN-gamma production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN-gamma/TNF-alpha double-producing CD8(+) T cells within the tumor. These results suggest that combination blockade of the PD-1/PD-L1- and CTLA-4-negative costimulatory pathways allows tumor-specific T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory.
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            Tumor-specific Th17-polarized cells eradicate large established melanoma.

            CD4+ T cells can differentiate into multiple effector subsets, but the potential roles of these subsets in anti-tumor immunity have not been fully explored. Seeking to study the impact of CD4+ T cell polarization on tumor rejection in a model mimicking human disease, we generated a new MHC class II-restricted, T-cell receptor (TCR) transgenic mouse model in which CD4+ T cells recognize a novel epitope in tyrosinase-related protein 1 (TRP-1), an antigen expressed by normal melanocytes and B16 murine melanoma. Cells could be robustly polarized into Th0, Th1, and Th17 subtypes in vitro, as evidenced by cytokine, chemokine, and adhesion molecule profiles and by surface markers, suggesting the potential for differential effector function in vivo. Contrary to the current view that Th1 cells are most important in tumor rejection, we found that Th17-polarized cells better mediated destruction of advanced B16 melanoma. Their therapeutic effect was critically dependent on interferon-gamma (IFN-gamma) production, whereas depletion of interleukin (IL)-17A and IL-23 had little impact. Taken together, these data indicate that the appropriate in vitro polarization of effector CD4+ T cells is decisive for successful tumor eradication. This principle should be considered in designing clinical trials involving adoptive transfer-based immunotherapy of human malignancies.
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              Synergism of Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and Depletion of Cd25+ Regulatory T Cells in Antitumor Therapy Reveals Alternative Pathways for Suppression of Autoreactive Cytotoxic T Lymphocyte Responses

              Therapeutic efficacy of a tumor cell–based vaccine against experimental B16 melanoma requires the disruption of either of two immunoregulatory mechanisms that control autoreactive T cell responses: the cytotoxic T lymphocyte–associated antigen (CTLA)-4 pathway or the CD25+ regulatory T (Treg) cells. Combination of CTLA-4 blockade and depletion of CD25+ Treg cells results in maximal tumor rejection. Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the frequency of tyrosinase-related protein 2180–188–specific CTLs detected in the periphery. Furthermore, tumor rejection is dependent on the CD8+ T cell subset. Our data demonstrate that the CTL response against melanoma antigens is an important component of the therapeutic antitumor response and that the reactivity of these CTLs can be augmented through interference with immunoregulatory mechanisms. The synergism in the effects of CTLA-4 blockade and depletion of CD25+ Treg cells indicates that CD25+ Treg cells and CTLA-4 signaling represent two alternative pathways for suppression of autoreactive T cell immunity. Simultaneous intervention with both regulatory mechanisms is therefore a promising concept for the induction of therapeutic antitumor immunity.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                22 October 2019
                2019
                : 10
                : 1201
                Affiliations
                [1] 1Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile , Santiago, Chile
                [2] 2Centro de Biotecnología Acuícola, Universidad de Santiago de Chile , Santiago, Chile
                [3] 3Escuela de Medicina, Facultad de Ciencias Médicas, Universidad de Santiago de Chile , Santiago, Chile
                [4] 4Departamento de Biología, Facultad de Ciencias, Universidad de Chile , Santiago, Chile
                [5] 5Millennium Institute Immunology and Immunotherapy, FOCIS Center of Excellence, Facultad de Ciencias Biológicas, Facultad de Medicina, Pontificia Universidad Católica de Chile , Santiago, Chile
                [6] 6Departamento de Salud, Universidad de Los Lagos , Osorno, Chile
                [7] 7Departamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago de Chile , Santiago, Chile
                [8] 8Laboratorio Biología Celular y Molecular, Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile , Santiago , Chile
                Author notes

                Edited by: Javier A. Bravo, Pontificia Universidad Católica de Valparaíso, Chile

                Reviewed by: Walter J. Storkus, University of Pittsburgh, United States; Shankar Munusamy, Drake University, United States

                *Correspondence: Claudio Acuña-Castillo, claudio.acuna@ 123456usach.cl

                This article was submitted to Translational Pharmacology, a section of the journal Frontiers in Pharmacology

                †These authors have contributed equally to this work

                Article
                10.3389/fphar.2019.01201
                6817581
                2b68fec9-fd55-43eb-aa44-bf0f57798ec8
                Copyright © 2019 Robles-Planells, Michelson, Mena, Escrig, Rojas, Sanchez-Guerrero, Hernández, Barrera-Avalos, Rojo, Sauma, Kalergis, Imarai, Fernández, Robles, Leiva-Salcedo, Santander, Escobar and Acuña-Castillo

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 27 December 2018
                : 17 September 2019
                Page count
                Figures: 7, Tables: 2, Equations: 0, References: 42, Pages: 11, Words: 5504
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                cancer,topic treatment,lithraea caustic,dth response,immunotherapy

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