Multiple mechanisms of immune evasion can coexist in melanoma tumor cell lines derived from the same patient

Real, Luis Miguel; Jiménez, Pilar; Kirkin, Alexei F.; Serrano, Antonio; García, Ana Isabel Morales; Cantón, Julia; Zeuthen, Jesper; Garrido, Federico; Ruiz‐Cabello, Francisco

doi:10.1007/s002620000154

Cited by 43 publications

(29 citation statements)

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“…One explanation is that the tumour microenvironment is so immunosuppressive that any incoming effector cell is impeded (Appay et al, 2006). Proposed mechanisms for melanoma-derived immunosuppression include the secretion of TGFb, IL-10 and IDO, which have been found in patients' blood, primary melanomas and sentinel lymph nodes (SLN) (Reed et al, 1994;Real et al, 2001;Lee et al, 2003Lee et al, , 2005Redondo et al, 2003). Additionally, levels were found to correlate with tumour progression and invasiveness (Reed et al, 1994;Conrad et al, 1999).…”

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confidence: 99%

Mechanisms of local immunosuppression in cutaneous melanoma

et al. 2007

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Cutaneous melanoma is highly immunogenic, yet primary melanomas and metastases develop successfully in otherwise immunocompetent patients. To investigate the local immunosuppressive microenvironment, we examined the presence of suppressor T lymphocytes and tolerising dendritic cells (DCs), the expression of immunosuppressive cytokines (IL-10, TGFb1 and TGFb2) and the enzyme indoleamine 2,3-dioxygenase (IDO) using qRT -PCR and immunohistochemistry in primary skin melanomas, negative and positive sentinel lymph nodes (SLN), and lymph nodes with advanced metastases. Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. They express transforming growth factor b receptor 1 (TGFbR1), and are therefore susceptible to TGFb1 and TGFb2 specifically expressed by primary melanoma. We found that expression of IDO and interleukin 10 (IL-10) increased with melanoma progression, with the highest concentration in positive SLN. We suggest that negative SLN contain immunosuppressive cells and cytokines, due to preconditioning by tolerogenic DCs migrating from the primary melanoma site to the SLN. In primary melanoma, TGFb2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFb1 may have a major effect. This mechanism of tumourassociated immunosuppression may inhibit the immune response to the tumour and may explain the discrepancy between the induction of systemic immunity by anti-melanoma vaccines and their poor performance in the clinic.

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confidence: 99%

Mechanisms of local immunosuppression in cutaneous melanoma

et al. 2007

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“…However, the principal mechanism of tumor escape is the loss, down-regulation or alteration of HLA profiles that may render the target cell unresponsive to CTL lysis, even if the cell expresses the appropriate tumor antigen. [13][14][15][16][17][18][19][20] Thus, in both situations, low frequency of a particular tumorassociated MHC-peptide complex, or downregulation of MHC expression on tumor cells, antibody-guided, tumor-specific targeting of class I MHC-peptide complexes onto tumor cells, as shown herein, can be an effective and efficient strategy to render cells more susceptible to lysis by the relevant, preselected, desirable HLA-A2-restricted CTLs.…”

Section: Discussionmentioning

confidence: 86%

“…[13][14][15][16][17][18][19][20] Even when a specific CTL response is demonstrated in patients, this response is low because the antitumor CTL population is rare, very infrequent and in some cases not functional or anergic. 42 Moreover, it is wellestablished that the number of MHC-peptide complexes on the surface of tumor cells that present a particular tumor-associated peptide is low.…”

Section: Discussionmentioning

confidence: 99%

“…[14][15][16][17] Defects in the HLA class I presentation may represent a major obstacle when trying to potentiate the activity of CTLs against tumors that underwent downregulation of MHC, and express, if any, low levels of MHC class I complexes. [18][19][20] To overcome these limitations, we have recently proposed a novel strategy for cancer immunotherapy that combines the advantage of the well-established tumor targeting properties of antitumor antibodies and their recombinant fragments (such as scFv and Fab) with the known efficient, specific and potent cytotoxic activity of CD8 T lymphocytes directed against highly antigenic MHC/peptide complexes. 21 In this approach, scFv fragments are genetically fused to a single-chain MHC class I molecule containing a selected antigenic peptide, in order to target the active MHC/peptide complex on tumor cells and induce their lysis by specific CTLs.…”

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confidence: 99%

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Selective antibody‐mediated targeting of class I MHC to EGFR‐expressing tumor cells induces potent antitumor CTL activity in vitro and in vivo

Novak

Noy

Oved

et al. 2006

Intl Journal of Cancer

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Epidermal growth factor receptor (EGFR) is highly overexpressed in many tumor types. We present a new fusion molecule that can target solid tumors that express EGFR. The fusion molecule combines the advantages of the well-established tumor targeting capabilities of high affinity recombinant fragments of antibodies with the known efficient, specific and potent killing ability of CD8 T lymphocytes directed against highly antigenic MHC/peptide complexes. A recombinant chimeric molecule was created by the genetic fusion of the scFv antibody fragment derived from the anti-EGFR monoclonal antibody C225, to monomeric single-chain HLA-A2 complexes containing immunodominant tumor or viralspecific peptides. The fusion protein can induce very efficiently CTL-dependent lysis of EGFR-expressing tumor cells regardless of the expression of self peptide-MHC complexes. Moreover, the molecule exhibited very potent antitumor activity in vivo in nude mice bearing preestablished human tumor xenografts. These in vitro and in vivo results indicate that recombinant scFv-MHCpeptide fusion molecules might represent a novel and powerful approach to immunotherapy of solid tumors, bridging antibody and T lymphocyte attack on cancer cells. ' 2006 Wiley-Liss, Inc.Key words: tumor immunotherapy; antibody targeting; T-cell; MHC Traditional cytotoxic approaches to treat solid tumor are often hindered by toxicity, lack of efficacy and development of resistance. In particular, there is a lack of viable options for patients with metastatic disease or with tumors that have progressed or recurred following conventional cytotoxic therapy. These limitations have resulted in a growing interest in developing therapies that more specifically target tumor cells while minimizing toxicity to healthy tissues. One such targeted approach exploits the use of the immune system known as immunotherapy. Cancer immunotherapy employs 2 major strategies: systemic injection of high-affinity monoclonal antibodies (mAbs) directed against cell surface tumor-associated antigens 1-2 and the potentiation of the cellular arm of the immune system, mainly through CD81 cytotoxic T lymphocytes. Antitumor antibodies that carry effector payloads such as toxins (immunotoxins) or cytokines are also potent molecules, which are being currently tested in various clinical trials. 3,4 Cellular-based strategies used are as follows: (i) active immunization of patients with antigens known to be recognized by T lymphocytes and activating them 5-10 and (ii) adoptive transfer therapies that enable the selection and activation of highly reactive Tcell subpopulations with improved antitumor activities. 10,11The adoptive transfer approach has recently demonstrated impressive results.10,11 Regression of metastatic melanoma was reported in patients undergoing adoptive transfer protocols with highly selected tumor-reactive T cells directed against over expressed self-derived differentiation antigens after a nonmyeloablative conditioning regimen. 12 The efficiency of T-cell-based immunotherapy approac...

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“…Mechanisms that may exist for the escape of tumors from immunosurveillance are of course not mutually exclusive but rather a combination of several different characteristics ( Figure) (Real et al, 2001): failure to express the major histocompatibility complex (MHC) antigen; decreased and heterogeneous expression of tumor antigen (TA); and abnormal expression of accessory molecules by tumor cells. In addition to these, many other factors allow tumor cells to escape immunosurveillance.…”

Section: Escape Mechanisms In Tumor Immunosurveillancementioning

confidence: 99%

Failure of immunological cells to eradicate tumor and cancer cells: an overview

Sharma¹,

Talukdar²,

Malik³

et al. 2014

Turk J Biol

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Inflammation can be broadly understood as a successive immune response of an organism's immune system towards nonnative or foreign antigens. This is a protective mechanism of the immune system, mediated by diverse immunological cells, to ensure homeostasis of an individual. Once activated, these immunological cells release a number of cytokines, chemokines, reactive oxygen species, reactive nitrogen species, histamines, prostaglandins, and other materials leading to inflammation. Tumor cells express altered proteins due to mutations of their genes, DNA modifications such as histone modification, DNA methylation, or other mechanisms of altered protein expression. The body's immunological cells actively recognize these altered proteins, now acting as tumor antigens, and eliminate the tumor cell; this is popularly known as tumor immunosurveillance. However, in unmanaged or inexorable circumstances, tumor cells escape from immunosurveillance mechanisms. This ultimately leads to the cascading events of cancer development and progression. T regulatory cells, tumor-associated macrophages, and myeloid-derived suppressor cells are pronounced cells involved in immunosuppression. These cells not only dodge the immune system's surveillance but also significantly increase the survival, proliferation, and metastasis rates of tumor cells. They hinder T cytotoxic activation by secreting inhibitory cytokines (which inhibit the antitumor activity of natural killer cells) along with dendritic cells and disrupt presentation of antigens, ultimately leading to cancer development. On their own, these cells have emerged as promising therapeutic targets in cancer immunotherapy. This review highlights some of the mechanisms by which these cells escape immunosurveillance and mediate immune suppression.

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Multiple mechanisms of immune evasion can coexist in melanoma tumor cell lines derived from the same patient

Cited by 43 publications

References 0 publications

Mechanisms of local immunosuppression in cutaneous melanoma

Mechanisms of local immunosuppression in cutaneous melanoma

Selective antibody‐mediated targeting of class I MHC to EGFR‐expressing tumor cells induces potent antitumor CTL activity in vitro and in vivo

Failure of immunological cells to eradicate tumor and cancer cells: an overview

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