Immune evasion in cancer: Mechanistic basis and therapeutic strategies

Vinay, D.S.,Ryan, E.P.,Pawelec, G.,Talib, W.H.,Stagg, J.,Elkord, E.,Lichtor, T.,Decker, W.K.,Whelan, R.L.,Kumara, H.M.C.S.,Signori, E.,Honoki, K.,Georgakilas, A.G.,Amin, A.,Helferich, W.G.,Boosani, C. Saunders Scientific Publications ; Academic Press 2015 SEMINARS IN CANCER BIOLOGY Vol.35 No.suppl

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through ''equilibrium'' and ''senescence'' before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection.

Cutaneous lesions in colorectal carcinoma: a rare presentation

( Vinay G Zanwar ),( Sunil V Pawar ),( Samit S Jain ),( Chitra S Nayak ),( Pravin M Rathi ) 대한장연구학회 2016 Intestinal Research Vol.14 No.1

Role of endogenous 4-1BB in the development of systemic lupus erythematosus

Vinay, Dass S.,Choi, Jae H.,Kim, Jung D.,Choi, Beom K.,Kwon, Byoung S. Blackwell Scientific Publications 2007 Immunology Vol.122 No.3

<P>Summary</P><P>Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies directed against nuclear antigens including nucleosomes and DNA. To determine the role of T-cell costimulatory molecule 4-1BB in the regulation of SLE, MRL-<I>Fas</I><SUP><I>lpr</I></SUP> (<I>lpr</I>) mice deficient in 4-1BB (<I>lpr</I>/4-1BB<SUP>–/–</SUP>) were generated and their disease phenotype was compared to that of control <I>lpr</I> mice. The main finding of this study is that the <I>lpr</I>/4-1BB<SUP>–/–</SUP> mice had more pronounced skin lesions which appeared earlier, increased lymphadenopathy, increased renal damage, and higher mortality than 4-1BB-intact control <I>lpr</I> mice. The increased severity of lesions in <I>lpr</I>/4-1BB<SUP>–/–</SUP> mice was closely associated with increases in CD4<SUP>+</SUP> T, CD3<SUP>+</SUP> B220<SUP>+</SUP> double-negative T cells, serum immunoglobulin, anti-dsDNA autoantibodies, and tissue immunoglobulin deposits. These data suggest that the 4-1BB−4-1BB ligand signalling pathway plays an important role in SLE and that deletion of 4-1BB confers susceptibility to <I>lpr</I> mice, leading to accelerated induction of disease and early mortality.</P>

Immunotherapy of cancer with 4-1BB.

Vinay, Dass S,Kwon, Byoung S American Association for Cancer Research, Inc 2012 Molecular Cancer Therapeutics Vol.11 No.5

<P>4-1BB (CD137), a member of the TNF receptor superfamily, is an activation-induced T-cell costimulatory molecule. Signaling via 4-1BB upregulates survival genes, enhances cell division, induces cytokine production, and prevents activation-induced cell death in T cells. The importance of the 4-1BB pathway has been underscored in a number of diseases, including cancer. Growing evidence indicates that anti-4-1BB monoclonal antibodies possess strong antitumor properties, which in turn are the result of their powerful CD8+ T-cell activating, IFN-γ producing, and cytolytic marker-inducing capabilities. In addition, combination therapy of anti-4-1BB with other anticancer agents, such as radiation, has robust tumor-regressing abilities against nonimmunogenic or poorly immunogenic tumors. Furthermore, the adoptive transfer of ex vivo anti-4-1BB-activated CD8+ T cells from previously tumor-treated animals efficiently inhibits progression of tumors in recipient mice that have been inoculated with fresh tumors. In addition, targeting of tumors with variants of 4-1BBL directed against 4-1BB also have potent antitumor effects. Currently, a humanized anti-4-1BB is in clinical trials in patients with solid tumors, including melanoma, renal carcinoma, and ovarian cancer, and so far seems to have a favorable toxicity profile. In this review, we discuss the basis of the therapeutic potential of targeting the 4-1BB-4-1BBL pathway in cancer treatment.</P>

Amelioration of mercury-induced autoimmunity by 4-1BB.

Vinay, Dass S,Kim, Jung D,Kwon, Byoung S American Association of Immunologists 2006 Journal of Immunology Vol.177 No.8

<P>In certain strains of mice, subtoxic doses of HgCl2 (mercuric chloride; mercury) induce a complex autoimmune condition characterized by the production of antinucleolar IgG Abs, lymphoproliferation, increased serum levels of IgG1/IgE Abs, and deposition of renal immune complexes. 4-1BB is an important T cell costimulatory molecule that has been implicated in T cell proliferation and cytokine production, especially production of IFN-gamma. To elucidate T cell control mediated by the 4-1BB signaling pathway in this syndrome, we assessed the effect of administering agonistic anti-4-1BB mAb on mercury-induced autoimmunity. Groups of A.SW mice (H-2s) received mercury/control Ig or mercury/anti-4-1BB or PBS alone. Anti-4-1BB mAb treatment resulted in a dramatic reduction of mercury-induced antinucleolar Ab titers, serum IgG1/IgE induction, and renal Ig deposition. These effects may be related to the present finding that anti-4-1BB mAb decreases B cell numbers and function. The anti-4-1BB mAb-treated mercury group also showed a marked reduction in Th2-type cytokines but an increase in Th1-type cytokines and chemokines. Increased IFN-gamma production due to anti-4-1BB mAb treatment appears to be responsible for the observed B cell defects because neutralization of IFN-gamma in vivo substantially restored B cell numbers and partly restored IgG1/IgE. Collectively, our results indicate that 4-1BB mAb can down-regulate mercury-induced autoimmunity by affecting B cell function in an IFN-gamma-dependent manner and thus, preventing the development of autoantibody production and tissue Ig deposition.</P>

TNF superfamily: Costimulation and clinical applications

Vinay, Dass S.,Kwon, Byoung S. Elsevier 2009 Cell biology international Vol.33 No.4

<P><B>Abstract</B></P><P>The molecules concerned with costimulation belong either to the immunoglobulin (Ig) or tumor necrosis factor (TNF) superfamily. The tumor necrosis superfamily comprises molecules capable of providing both costimulation and cell death. In this review we briefly summarize certain TNF superfamily receptor–ligand pairs that are endowed with costimulatory properties and their importance in health and disease.</P>

Origins and functional basis of regulatory CD11c⁺CD8⁺ T cells

Vinay, Dass S.,Kim, Chang H.,Choi, Beom K.,Kwon, Byoung S. WILEY-VCH Verlag 2009 European journal of immunology Vol.39 No.6

<P>Previously, we showed that CD11c defines a novel subset of CD8<SUP>+</SUP> T cells whose in vivo activity is therapeutic for arthritis; however, the mechanisms directing their development, identity of their precursors, and basis of their effector function remain unknown. Here, we show that the novel subset develops from CD11c<SUP>surface−</SUP>CD8<SUP>+</SUP> T cells and undergoes robust expansion in an antigen- and 4-1BB (CD137)-dependent manner. CD11c<SUP>+</SUP>CD8<SUP>+</SUP> T cells exist in naïve mice (<3%) with limited suppressive activity. Once activated, they suppress CD4<SUP>+</SUP> T cells in vivo and in vitro. Suppression of CD4<SUP>+</SUP> by CD11c<SUP>+</SUP>CD8<SUP>+</SUP> T cells is related to an increase in IDO activity induced in competent cells via the general control non-derepressible-2 pathway. CD11c<SUP>+</SUP>CD8<SUP>+</SUP> T cells are refractory to the effect of IDO but constrict in a novel 1-methyl D,L-tryptophan-dependent mechanism resulting in reversal of their suppressive effects. Thus, our data uncover, for the first time, the origin, development, and basis of the suppressive function of this novel CD11c<SUP>+</SUP>CD8<SUP>+</SUP> T-cell subpopulation that has many signature features of Treg.</P>

Immunotherapy Targeting 4-1BB and Its Ligand

Vinay, Dass S.,Kwon, Byoung S. Springer-Verlag 2006 International journal of hematology Vol.83 No.1

<P>T-cell activation in the absence of costimulation is futile because T-cells deprived of costimulatory signals enter a state of unresponsiveness or anergy. The interaction of 4-1BB and 4-1BB ligand (4-1BBL) activates an important costimulatory pathway with diverse and important roles in immune regulation. Signals relayed through 4-1BB generate strong CD8(+) T-cell responses rather than CD4(+) T-cell responses; this action results in cytokine induction and promotes T-cell survival. In recent years, 4-1BB-mediated immune regulation has gained great significance because of the seemingly contradictory dual roles of agonistic anti-4-1BB in vivo disease models. To date, agonistic 4-1BB monoclonal antibody has shown therapeutic potential against a variety of tumors, CD4(+) T-cell-mediated autoimmune diseases, and chronic graft-versus-host disease. In addition, blockade of 4-1BB/4-1BBL interaction has produced therapeutic effects against coxsackievirus-induced myocardial inflammation, herpetic stromal keratitis, and graft rejection. We propose that the dual roles of agonistic anti-4-1BB--an enhanced effector function and a suppressor function--are mediated by a novel CD11c(+)CD8(+) T-cell population.</P>

Toxicity and dose determination of quillaja saponin, aluminum hydroxide and squalene in olive flounder (Paralichthys olivaceus)

Vinay, T.N.,Park, C.S.,Kim, H.Y.,Jung, S.J. Elsevier 2014 Veterinary immunology and immunopathology Vol. No.

Adjuvants are substances added to vaccines to enhance the immune response of a given antigen. Most of the adjuvants are toxic at certain doses, and toxicity varies in different species. Moreover, there are no standard dosage limits set for adjuvant use in fish vaccines. We evaluated the acute toxicity, serum enzymes (AST/ALT) indicating hepatic injury and histopathological changes due to intra-peritoneal administration of different concentrations of a panel of adjuvants including quillaja saponin, aluminum hydroxide, squalene emulsion and Freund's incomplete adjuvant (FIA) with a dose ranging study of saponin (500, 160, 50, 16 and 5μgfish<SUP>-1</SUP>), aluminum hydroxide (5000, 1600, 500, 160 and 50μgfish<SUP>-1</SUP>), squalene emulsion (20, 10 and 5%), and FIA to determine the acceptable dosage for vaccination in olive flounder (Paralichthys olivaceus) fingerlings measuring 4.66+/-0.41g, 8.47+/-0.42cm. Saponin was highly toxic with a LD<SUB>50</SUB> of approximately 105μgfish<SUP>-1</SUP> (22.4mgkg<SUP>-1</SUP>) causing severe histological damage and AST level was high at dose above 16μgfish<SUP>-1</SUP> and ALT, specific for liver damage was high only at 160μgfish<SUP>-1</SUP> (11U/L) and was safe at 5μgfish<SUP>-1</SUP>. Aluminum hydroxide was toxic at 5000μgfish<SUP>-1</SUP> and was acceptable at dose below 1600μgfish<SUP>-1</SUP> with moderate histology and AST/ALT levels similar with control. Squalene emulsion showed increased inflammation at 20% and 10% emulsions and the inflammatory response was mild at a concentration of 5% oil emulsion and AST/ALT levels being similar to control in 10% and 5% emulsions and elevated in 20% on both sampling days. FIA was not lethal, but induced severe inflammation at injection site and around blood vessels. In comparison to FIA, saponin found to be safe at dose of 5μgfish<SUP>-1</SUP>, aluminum hydroxide below 1600μgfish<SUP>-1</SUP>, and squalene at 5% emulsion and could be accepted for vaccination studies. These results provide an insight for the selection of safer dose of adjuvants for intra-peritoneal vaccination of olive flounder.

PDCA Expression by B Lymphocytes Reveals Important Functional Attributes

Vinay, D.S.,Kim, C.H.,Chang, K.H.,Kwon, B.S. American Association of Immunologists 2010 JOURNAL OF IMMUNOLOGY Vol.184 No.2