Molecular Insights for Optimizing T Cell Receptor Specificity Against Cancer

Abstract

Cytotoxic CD8 T cells mediate immunity to pathogens and they are able to eliminate malignant cells. Immunity to viruses and bacteria primarily involves CD8 T cells bearing high affinity T cell receptors (TCRs), which are specific to pathogen-derived (non-self) antigens. Given the thorough elimination of high affinity self/tumor-antigen reactive T cells by central and peripheral tolerance mechanisms, anti-cancer immunity mostly depends on TCRs with intermediate-to-low affinity for self-antigens. Because of this, a promising novel therapeutic approach to increase the efficacy of tumor-reactive T cells is to engineer their TCRs, with the aim to enhance their binding kinetics to pMHC complexes, or to directly manipulate the TCR-signaling cascades. Such manipulations require a detailed knowledge on how pMHC-TCR and co-receptors binding kinetics impact the T cell response. In this review, we present the current knowledge in this field. We discuss future challenges in identifying and targeting the molecular mechanisms to enhance the function of natural or TCR-affinity optimized T cells, and we provide perspectives for the development of protective anti-tumor T cell responses.

Chimeric PD-1:28 Receptor Upgrades Low-Avidity T cells and Restores Effector Function of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

“…Experimentally generated high-affinity TCRs might be advantageous by boosting effector function and proliferation, thereby persisting longer and in larger numbers as compared with T cells with low-affinity TCRs, but they may also bear an increased risk of unwanted toxicities (3,4,(9)(10)(11)(12). Low-avidity T cells would gain value if their effector functions could be enhanced, as they are reported to be less susceptible to tolerization and may represent a lower toxicity risk (3,4,13,14).…”

“…Although there is consensus that durable antitumor responses require highly active T cells, it is not clear how this is best achieved. At least two major impediments have been identified that impinge upon achieving this prerequisite: inherent intermediate-to low-affinity T-cell receptors (TCR) of antitumor T cells that may not mount a successful tumor-specific response (3,4), and functional inactivation of T cells in the tumor milieu (5)(6)(7)(8).…”

TCR-ligand dissociation rate is a robust and stable biomarker of CD8+ T cell potency

“…The functional avidity of T cells is primarily controlled by the strength of TCR-pMHC interactions, a key parameter shown to impact on numerous aspects of T cell biology, including their thymic selection (21), activation and differentiation (22), autoimmune pathogenicity (23), and protection against infection and cancer (24). In fact, TCR-pMHC binding avidity may offer a key metric by which the quality of the T cell response can be directly evaluated, since it controls T cell activation, differentiation, and functional efficacy (25).…”

Vaccination with LAG-3Ig (IMP321) and Peptides Induces Specific CD4 and CD8 T-Cell Responses in Metastatic Melanoma Patients—Report of a Phase I/IIa Clinical Trial

“…5B) were stable over time (data not shown). Theoretically, higher intensity tetramer staining could be associated to a higher expression at the surface level of the TCR and/or the co-receptor (CD4), and/or to a higher TCR avidity (35,36). We next measured the expression level of TCR and CD4 separately, in order to avoid competition of the staining antibodies.…”