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T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)-mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagentstermed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth in vivo. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy., Harnessing the power of adaptive immunity to combat cancer has been a long-term goal of translational immunotherapy. However, although many avenues in this field have been explored over the past [...]

Toll-like receptor 9 (TLR9) agonists have gained traction in recent years as potential adjuvants for the induction of adaptive immune responses. It has nonetheless remained unclear to what extent such ligands can facilitate the priming events that generate antigen-specific effector and/or memory CD8 + T-cell populations. We used an established in vitro model to prime naive precursors from human peripheral blood mononuclear cells in the presence of various adjuvants, including CpG ODN 2006, a synthetic oligonucleotide TLR9 ligand (TLR9L). Unexpectedly, we found that TLR9L induced a suboptimal inflammatory milieu and promoted the antigen-driven expansion and functional maturation of naive CD8 + T cells ineffectively compared with either ssRNA40 or 2'3'-cGAMP, which activate other pattern recognition receptors (PRRs). TLR9L also inhibited the priming efficacy of 2'3'-cGAMP. Collectively, these results suggest that TLR9L is unlikely to be a good candidate for the optimal induction of de novo CD8 + T-cell responses, in contrast to adjuvants that operate via discrete PRRs.

CD8 + T-cell expansions are the primary manifestation of T-cell large granular lymphocytic leukemia (T-LGLL), which is frequently accompanied by neutropenia and rheumatoid arthritis, and also occur as a secondary phenomenon in leukemia patients treated with dasatinib, notably in association with various drug-induced side-effects. However, the mechanisms that underlie the genesis and maintenance of expanded CD8 + T-cell receptor (TCR)-Vβ + populations in these patient groups have yet to be fully defined. In this study, we performed a comprehensive phenotypic and clonotypic assessment of expanded (TCR-Vβ + ) and residual (TCR-Vβ - ) CD8 + T-cell populations in T-LGLL and dasatinib-treated chronic myelogenous leukemia (CML) patients. The dominant CD8 + TCR-Vβ + expansions in T-LGLL patients were largely monoclonal and highly differentiated, whereas the dominant CD8 + TCR-Vβ + expansions in dasatinib-treated CML patients were oligoclonal or polyclonal, and displayed a broad range of memory phenotypes. These contrasting features suggest divergent roles for antigenic drive in the immunopathogenesis of primary versus dasatinib-associated CD8 + TCR-Vβ + expansions.

CD8 + T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8 + T-cell population are not desirable because the associated lack of specificity can lead to unwanted consequences, most notably an enhanced susceptibility to infection. Here, we show that autoreactive CD8 + T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR). In contrast, pathogen-specific CD8 + T-cells are relatively CD8-independent. These generic differences relate to an intrinsic dichotomy that segregates self-derived and exogenous antigen-specific TCRs according to the monomeric interaction affinity with cognate peptide-major histocompatibility complex class I (pMHCI). As a consequence, "blocking" anti-CD8 antibodies can suppress autoreactive CD8 + T-cell activation in a relatively selective manner. These findings provide a rational basis for the development and in vivo assessment of novel therapeutic strategies that preferentially target disease-relevant autoimmune responses within the CD8 + T-cell compartment.