Manipulating the T-Cell Receptor Yields Promising Immunotherapies

Jane de Lartigue, PhD
Published: Tuesday, May 01, 2018
Components of the T-cell receptor (TCR) complex, which links antigen recognition with T-cell activity and effector function, are being exploited for several types of cancer immunotherapy. Although these strategies have not received the same level of attention as blockbuster immunotherapies such as checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapies, they have made steady progress over the past few years, and many novel agents are undergoing clinical testing.

Researchers also are working on ImmTACs, a new class of bispecific drugs that combines the advantageous properties of targeting intracellular antigens and the benefits of a soluble drug format without the time-consuming and labor-intensive manufacturing requirements of cell-based therapies.

Immune Therapies Exploit T Cells

As our understanding of the dual role of the immune system in both restraining and promoting cancer has evolved, so too has our ability to harness its components to yield groundbreaking therapies that augment the antitumor immune response and offer the promise of long-lasting tumor regression.

TCR-Mediated T-Cell Activation

T-cell activation is dependent on the TCR upon its surface, which engages the antigen-MHC complex on APCs, triggering a cascade of signaling molecules within the cell that ultimately promotes the proliferation of T cells and the acquisition of the properties that enable their effector functions.

 

Figure 1. Basic Structure of the TCR

  The constituent protein chains are made up of a variable and constant region that protrudes from the cell, a portion that spans the membrane, and a short tail inside the cell. Unlike most transmembrane receptors, the tail of the TCR has no inherent signaling activity. Instead, the TCR forms a complex with the CD3 protein family consisting of CD3δ, γ, ε, and ζ, which link the antigen recognition abilities of the TCR with the activation of downstream signaling pathways.


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Community Practice Connections™: New Directions in Advanced Cutaneous Squamous Cell Carcinoma: Emerging Evidence of ImmunotherapyAug 13, 20191.5
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