Evasion strategies that specifically impair V9V2 T cell functions can involve diverse immunosuppressive mediators produced in the tumor microenvironment, as, for example, transforming growth factor-, prostaglandins, kynurenins, or potassium (86C89). All of the above pitfalls may be partly overcome by utilization of the adoptive cell transfer of following injection of Zoledronate and IL-2. Other studies have shown that it is possible to sustain injected V9V2 T cells without IL-2 supplementation, probably relying on IL-15 (91) or on IL-18 (92, 93) spontaneously produced by the host. Can We Improve T Cell-Based Tumor Immunotherapy? T cells can be redirected to the cancer cell using antibodies (Figure ?(Figure2).2). BCR-ABL-IN-2 which is highly active upon infection or tumor transformation. Aminobisphosphonates (n-BPs), which inhibit farnesyl pyrophosphate synthase, a downstream enzyme of the mevalonate pathway, cause accumulation of upstream PAgs and therefore promote T cell activation. T cells have distinctive features that justify their utilization in antitumor immunotherapy: they do not require MHC restriction and are BCR-ABL-IN-2 less dependent that T cells on co-stimulatory signals, produce cytokines with known antitumor effects as interferon- and tumor necrosis factor- and display cytotoxic and antitumor activities and in mouse models or after adoptive transfer of a broad array of tumor cells, while sparing normal cells Rabbit Polyclonal to RRS1 (34), and display antitumor activity in mouse models (34). The cytotoxic activity of T cells against tumor cells is strictly dependent on augmented production of PAgs (38), which partly relies on increased expression of HMGCR (38). Moreover, intracellular PAgs levels can be substantially increased by n-BPs (13C15, 38), thereby promoting activation of V9V2 T cells (38). Killing may also be reinforced by the tumor cell expression of NCRs (39) and/or NKG2D ligands (such as MICA, MICB, and ULBPs) (40C42) or by antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by CD16 interacting with antibody-coated tumor cells (43) (Figure ?(Figure11). Open in a separate window Figure 1 Tumor cell ligands recognized by human T cells. The upper and lower panels show stimulatory and inhibitor signals delivered by tumor cells to V1 (left) and V2 (right) T cell subsets. V9V2 T cells recognize their TCR non-peptidic phosphoantigens (PAgs) and BTN3A1, while V1 T cell receptor (TCR) ligands are not defined yet. Both T cell subsets constitutively express surface natural cytotoxicity cell receptors (NCRs) that bind MICA/MICB and ULBPs, frequently expressed on tumor cells. Upon activation, V9v2 T BCR-ABL-IN-2 cells express fragment crystallizable receptor for IgG (FcRIII; also known as CD16) that can bind therapeutic antibodies and mediate antibody-dependent cell-mediated cytotoxicity phenomena. Inhibitor signals delivered by tumor cells have not been well characterized. MICA/B, MHC class I-related chain A/B; ULBP, UL16-binding protein; BTN3A1, butyrophilin 3A1. Whatever the mechanism of T cell recognition of tumor target cells, killing involves the perforin/granzyme (44) and TNF-related apoptosis-inducing ligand (TRAIL) (45) pathways, and Fas/FasL interaction (46). The choice of the mechanism is mostly dictated by the nature of the target cell itself (47). For instance, we previously found that colon cancer stem cells (CSCs), which are typically resistant to T cell-mediated cytotoxicity, are efficiently killed upon sensitization with Zoledronate (48). Killing of Zoledronate-treated colon CSCs was abrogated by anti-CD3 or anti- TCR monoclonal antibodies (mAbs), or mevastatin, which inhibits HMGCR and prevents PAg accumulation, and by Concanamycin A that blocks degranulation, indicating that V9V2 T cells recognize Zoledronate-treated colon CSCs by the TCR interacting with PAgs and utilize the perforin pathway to kill them (48). The colon CSCs are usually resistant also to chemotherapy, but we unexpectedly found that pretreatment with 5-Fluorouracil and Doxorubicin sensitizes colon CSCs to killing by V9V2 T cells. However, killing of chemotherapy-sensitized colon CSCs by V9V2 T cells was inhibited by anti-NKG2D mAb and by blocking TRAIL interaction with its death receptor 5 (DR5), indicating that V9V2 T cells recognize chemotherapy-treated colon CSCs by NKG2D interaction with MICA/B or ULBPs and kill them through mechanisms involving TRAIL interaction with DR5 (49). (4) In order for T lymphocytes to interact with tumor cells they should be capable to infiltrate tumors. Tumor-infiltrating leukocytes are found in a several different solid tumors (50) and include both myeloid (granulocytes, macrophages, and myeloid-derived suppressor cells) and lymphoid (T, B, and NK) cells, each of which impacts differently on tumor.