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.

Collagen type II-induced arthritis is a CD4(+) T-cell-dependent chronic inflammation in susceptible DBA/1 mice and represents an animal model of human rheumatoid arthritis. We found that development of this condition, and even established disease, are inhibited by an agonistic anti-4-1BB monoclonal antibody. Anti-4-1BB suppressed serum antibodies to collagen type II and CD4(+) T-cell recall responses to collagen type II. Crosslinking of 4-1BB evoked an antigen-specific, active suppression mechanism that differed from the results of blocking the interaction between 4-1BB and its ligand, 4-1BBL. Anti-4-1BB monoclonal antibodies induced massive, antigen-dependent clonal expansion of CD11c(+)CD8(+) T cells and accumulation of indoleamine 2,3-dioxygenase in CD11b(+) monocytes and CD11c(+) dendritic cells. Both anti-interferon-gamma and 1-methyltryptophan, a pharmacological inhibitor of indoleamine 2,3-dioxygenase, reversed the anti-4-1BB effect. We conclude that the suppression of collagen-induced arthritis was caused by an expansion of new CD11c(+)CD8(+) T cells, and that interferon-gamma produced by these cells suppresses antigen-specific CD4(+) T cells through an indoleamine 2,3-dioxygenase-dependent mechanism.

TR6 (decoy receptor3The members of the tumor necrosis factor (TNF) 1 family are involved in regulating diverse biological activities such as regulation of cell proliferation, differentiation, cell survival, cell death, cytokine production, lymphocyte co-stimulation, and isotype switching (1, 2). Receptors in this family share a common structural motif in their extracellular domains consisting of multiple cysteine-rich repeats of approximately 30 -40 amino acids (3). While TNFR1, CD95/Fas/APO-1, DR3/TRAMP/ APO-3, DR4/TRAIL-R1/APO-2, DR5/TRAIL-R2, and DR6 receptors contain a conserved intracellular motif of ϳ80 amino acids called death domain, associated with the activation of apoptotic signaling pathways, other members, which contain a low sequence identity in the cytoplasmic domains, stimulate the transcription factors NF-B and AP-1 (1-3).Most TNF receptors contain a functional cytoplasmic domain. However, some members of the TNFR superfamily do not have cytoplasmic domains and are secreted, such as osteoprotegerin (OPG) (4), or linked to the membrane through a glycophospholipid tail, such as TRID/DcR1/TRAIL-R3 (5, 6). Viral open reading frames encoding soluble TNFRs have also been identified, such as SFV-T2 (7), Va53 (8), G4RG (9), and crmB (3).By searching an expressed sequence tag (EST) data base, a new member of the TNFR superfamily was identified, named TR6, and was characterized as a soluble cognate receptor for LIGHT and FasL/CD95L. LIGHT and FasL mediate the apoptosis, which is the most common physiological form of cell death and occurs during embryonic development, tissue remodeling, immune regulation, and tumor regression.LIGHT is highly induced in activated T lymphocytes and macrophages. LIGHT was characterized as a cellular ligand for HVEM/TR2 and LT␤R (10). HVEM/TR2 is a receptor for herpes simplex virus type 1 (HSV-1) entry into human T lymphoblasts. The soluble form of HVEM/TR2-Fc and antibodies to HVEM/ TR2 were shown to inhibit a mixed lymphocyte reaction, suggesting a role for this receptor or its ligand in T lymphocyte proliferation (10 -12). The level of LT␤R expression is prominent on epithelial cells but is absent in T and B lymphocytes. Signaling via LT␤R triggers cell death in some adenocarcinomas (13). LIGHT produced by activated lymphocytes could evoke immune modulation from hematopoietic cells expressing only HVEM/TR2 and induce apoptosis of tumor cells, which express both LT␤R and HVEM/TR2 receptors (14,15).FasL is one of the major effectors of cytotoxic T lymphocytes and natural killer cells. It is also involved in the establishment of peripheral tolerance in the activation-induced cell death of lymphocytes. Moreover, expression of FasL in nonlymphoid and tumor cells contributes to the maintenance of immune privilege of tissues by preventing the infiltration of Fas-sensitive lymphocytes (16). FasL is also processed and shed from the surface of human cells (17).Here we demonstrate that TR6 (DcR3), a new member of the TNFR superfamily, binds LIGHT and FasL. Therefore TR6 may act as a...

4-1BB, a T cell costimulatory receptor, prolongs CD8+ T cell survival. In these studies, 4-1BB stimulation was shown to increase expression of the antiapoptotic genes bcl-xL and bfl-1 via 4-1BB-mediated NF-κB activation. This signaling pathway was specifically inhibited by PDTC and was different from the pathways that enhanced CD8+ T cell proliferation. The results suggest a role for the antiapoptotic activities of Bcl-xL and Bfl-1 proteins in 4-1BB-mediated CD8+ T cell survival in vivo.