NK1.1+ Cells and CD8+ T Cells Mediate the Antitumor Activity of Cl-IB-MECA in a Mouse Melanoma Model (original) (raw)
Related papers
Adoptive Immunotherapy with Cl-IB-MECA-Treated CD8+ T Cells Reduces Melanoma Growth in Mice
PLoS ONE, 2012
Cl-IB-MECA is a selective A3 adenosine receptor agonist, which plays a crucial role in limiting tumor progression. In mice, Cl-IB-MECA administration enhances the anti-tumor T cell-mediated response. However, little is known about the activity of Cl-IB-MECA on CD8+ T cells. The aim of this study was to investigate the effect of ex vivo Cl-IB-MECA treatment of CD8+ T cells, adoptively transferred in melanoma-bearing mice. Adoptive transfer of Cl-IB-MECA-treated CD8+ T cells or a single administration of Cl-IB-MECA (20 ng/mouse) inhibited tumor growth compared with the control group and significantly improved mouse survival. This was associated with the release of Th1-type cytokines and a greater influx of mature Langerin+ dendritic cells (LCs) into the tumor microenvironment. CD8+ T cells treated with Cl-IB-MECA released TNF-a which plays a critical role in the therapeutic efficacy of these cells when injected to mice. Indeed, neutralization of TNF-a by a specific monoclonal Ab significantly blocked the anti-tumor activity of Cl-IB-MECA-treated T cells. This was due to the reduction in levels of cytotoxic cytokines and the presence of fewer LCs. In conclusion, these studies reveal that ex vivo treatment with Cl-IB-MECA improves CD8+ T cell adoptive immunotherapy for melanoma in a TNF-a-dependent manner.
Cancer Research, 2006
Adenosine is an important signaling molecule that regulates multiple physiologic processes and exerts major anti-inflammatory actions. Tumors have high concentrations of adenosine, which could inhibit the function of tumor-infiltrating lymphoid cells. We investigated the ability of adenosine and its stable analogue 2-chloroadenosine (CADO) to inhibit cytokine production and cytotoxic activity of lymphokine-activated killer (LAK) cells and determined whether both these effects are initiated via a common pathway. CADO strongly inhibited cytotoxic activity of LAK cells and attenuated the production of IFN-;, granulocyte macrophage colony-stimulating factor, tumor necrosis factor A, and macrophage inflammatory protein-1A by LAK cells stimulated by cross-linking of the Ly49D receptor. These inhibitory effects were associated with the ability of CADO to stimulate cyclic AMP (cAMP) production and activate protein kinase A (PKA). Using cAMP analogues with different affinities for the A and B sites of the regulatory subunits of PKA types I and II, we found that activation of PKA I, but not PKA II, mimicked the inhibitory effects of CADO on LAK cell cytotoxic activity and cytokine production. Inhibitors of the PKA catalytic subunits (H89 and PKI 14-22 peptide) failed to abrogate the inhibitory effects of CADO whereas Rp-8-Br-cAMPS, an antagonist of the RI subunit, blocked the inhibitory effects of CADO. We conclude that the inhibitory effects of adenosine are probably mediated via cAMP-dependent activation of the RI subunits of PKA I but are independent of the catalytic activity of PKA. Tumor-produced adenosine could be a potent tumor microenvironmental factor inhibiting the functional activity of tumor-infiltrating immune cells. (Cancer Res 2006; 66(15): 7758-65) Requests for reprints:
Journal of Experimental Medicine, 1999
Natural killer (NK) receptor signaling can lead to reduced cytotoxicity by NK cells and cytolytic T lymphocytes (CTLs) in vitro. Whether T cells are inhibited in vivo remains unknown, since peptide antigen-specific CD8 ϩ T cells have so far not been found to express NK receptors in vivo. Here we demonstrate that melanoma patients may bear tumor-specific CTLs expressing NK receptors. The lysis of melanoma cells by patient-derived CTLs was inhibited by the NK receptor CD94/NKG2A. Thus, tumor-specific CTL activity may be decreased through NK receptor triggering in vivo.
Cancer Research, 2012
Natural killer (NK) cells play a key role in tumor immune surveillance. However, adoptive immunotherapy protocols using NK cells have shown limited clinical efficacy to date, possibly due to tumor escape mechanisms that inhibit NK cell function. In this study, we analyzed the effect of coculturing melanoma cells and NK cells on their phenotype and function. We found that melanoma cells inhibited the expression of major NK receptors that trigger their immune function, including NKp30, NKp44, and NKG2D, with consequent impairment of NK cellmediated cytolytic activity against various melanoma cell lines. This inhibitory effect was primarily mediated by indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2). Together, our findings suggest that immunosuppressive barriers erected by tumors greatly hamper the antitumor activity of human NK cells, thereby favoring tumor outgrowth and progression. Cancer Res; 72(6); 1407-15. Ó2012 AACR.
Cancer Research, 2007
The goal of this study was to investigate the effects of adenosine and its stable analogue 2-chloroadenosine (CADO) on the cytotoxic activity and cytokine production by human antimelanoma specific CD8 + and CD4 + T-helper type 1 (Th1) clones. The cytotoxic activity of CD8 + T cells was inhibited by adenosine and CADO. Using Lab MAP multiplex technology, we found that adenosine inhibits production of various cytokines and chemokines by CD8 + and CD4 + T cells. Studies with CGS21680, a specific agonist of adenosine A 2A receptor (AdoRA 2A ), and ZM241385, an AdoRA 2 -selective antagonist, indicate that the inhibitory effects of adenosine are mediated via cyclic AMP (cAMP)-elevating AdoRA 2A , leading to protein kinase A (PKA) activation. Using cAMP analogues with different affinities for the A and B sites of the regulatory subunits of PKAI and PKAII, we found that activation of PKAI, but not of PKAII, mimicked the inhibitory effects of adenosine on T-cell cytotoxic activity and cytokine production. Inhibitors of the PKA catalytic subunits (H89 and PKA inhibitor peptide 14-22) failed to abrogate the inhibitory effects of CADO. In contrast, Rp-8-Br-cAMPS that antagonizes binding of cAMP to the regulatory I subunit and PKA activation was efficient in blocking the inhibitory effect of adenosine on the functional activity of T cells. Our findings on the ability of adenosine to inhibit the effector function of antimelanoma specific T cells suggest that intratumor-produced adenosine could impair the function of tumor-infiltrating T lymphocytes. Thus, blocking the inhibitory activity of tumor-produced adenosine might represent a new strategy for improvement of cancer immunotherapy. [Cancer Res 2007;67(12):5949-56] Requests for reprints:
Journal of Immunotherapy, 2011
NK cells have been shown to mediate important immunoregulatory "helper" functions in addition to their cytolytic activity. In particular, NK cells are capable of preventing maturation-related DC "exhaustion", inducing the development of "type-1 polarized" mature DCs with an enhanced ability to produce IL-12p70, a factor essential for type-1 immunity and effective anti-cancer responses. Here we show that the NK cell-mediated type-1 polarization of DCs can be applied in the context of patients with advanced cancer to enhance the efficacy of DCs in inducing tumorspecific CTLs. NK cells isolated from late-stage (stage III and IV) melanoma patients responded with high IFNγ production and the induction of type-1-polarized DCs upon exposure to defined combinations of stimulatory agents, including IFNα plus IL-18. The resulting DCs showed strongly-enhanced IL-12p70 production upon subsequent T cell interaction, compared to immature (i)DCs (average of 19-fold enhancement) and non-polarized IL-1β/TNF-α/IL-6/PGE 2 -matured "standard" (s)DCs (average of 215-fold enhancement). Additional inclusion of poly-I:C during NK-DC co-cultures optimized the expression of CD80, CD86, CD40, and HLA-DR on the resulting NK DC1s, increased their CCR7-mediated migratory responsiveness to the lymph nodeassociated chemokine CCL21, and further enhanced their IL-12-producing capacity. When compared in vitro to iDCs and non-polarized sDCs, NK DC1s were superior in inducing functional melanoma-specific CTLs capable of recognizing multiple melanoma-associated antigens and killing melanoma cells. These results indicate that the helper function of NK cells can be utilized in clinical settings to improve the effectiveness of DC-based cancer vaccines.
Neoplasia (New York, N.Y.), 2013
The A2b receptor (A2bR) belongs to the adenosine receptor family. Emerging evidence suggest that A2bR is implicated in tumor progression in some murine tumor models, but the therapeutic potential of targeting A2bR in melanoma has not been examined. This study first shows that melanoma-bearing mice treated with Bay 60-6583, a selective A2bR agonist, had increased melanoma growth. This effect was associated with higher levels of immune regulatory mediators interleukin-10 (IL-10) and monocyte chemoattractant protein 1 (MCP-1) and accumulation of tumor-associated CD11b positive Gr1 positive cells (CD11b(+)Gr1(+)) myeloid-derived suppressor cells (MDSCs). Depletion of CD11b(+)Gr1(+) cells completely reversed the protumor activity of Bay 60-6583. Conversely, pharmacological blockade of A2bR with PSB1115 reversed immune suppression in the tumor microenvironment, leading to a significant melanoma growth delay. PSB1115 treatment reduced both levels of IL-10 and MCP-1 and CD11b(+)Gr1(+) cell ...
Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model
American journal of cancer research, 2014
Combination therapies for melanoma that target immune-regulatory networks are entering clinical practice, and more are under investigation in preclinical or clinical studies. Adenosine plays a key role in regulating melanoma progression. We investigated the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody (mAb) in combination with either modulators of adenosine receptors (AR) activation or an inhibitor of adenosine production in a murine model of melanoma. We found that treatment with APCP, selective inhibitor of the adenosine-generating nucleotidase CD73, enhanced the activity of anti-CTLA4 mAb, by improving tumor immune response. Blockade of the adenosine A2a receptor (A2aR), which plays a critical role in the regulation of T-cell functions, significantly reduced melanoma growth. Most importantly, combination therapy including an A2aR antagonist with anti-CTLA4 mAb markedly inhibited tumor growth and enhanced anti-tumor immune responses. Targeting A3R...
Cancer Immunology, Immunotherapy, 2006
In recent years, studies on the molecular and cellular mechanisms of immune responses against melanoma have contributed to a better understanding of how these tumours can be recognised by cytotoxic cells and the mechanisms they have developed to escape from innate and adaptive immunity. Lysis of melanoma cells by natural killer (NK) cells and cytolytic T cells is the result of a fine balance between signals transmitted by activating and inhibitory receptors. In addition to the T cell receptor, these were initially described as NK cellassociated receptors (NKRs) and were later also found on subsets of T lymphocytes, particularly effectormemory and terminally differentiated CD8 T cells. An increase of NKR + CD8 + T cells has been found in melanoma patients, correlating with the expansion of differentiated effector CD8 + CD28 null CD27 null T cells. NKRs can regulate the lysis of target cells expressing appropriate ligands. Activating receptors recognise ligands on tumours whereas inhibitory receptors are specific for MHC class I antigens and sense missing self. Altered expression of MHC class I antigens is frequently found on melanoma cells, preventing recognition by specific cytolytic T cells but favouring NK cell recogni-tion. Changes in the expression of NKR-ligands in melanoma contribute in explaining the differences in the capacity of cytotoxic immune cells to control melanoma growth and dissemination.