Harnessing an organism’s immune system to fight a disease such as cancer is a powerful approach. In 2018 James Allison and Tasuku Honjo received the Nobel Prize in Physiology or Medicine for their lifetime work on two key immune checkpoint proteins displayed on the surface of T cells. These cell-surface receptors bind certain ligands displayed on other cells such as antigen-presenting cells (APCs) and recognize them as self, which leads to the attenuation of T cell activity and puts a brake on the immune response. The researchers independently showed during decades of work that preventing these receptors on T cells from binding their ligands on APCs or tumor cells lifts the block and triggers an attack on the tumor cells.

Getting at T cell receptor diversity. Credit: Marina Corral Spence/Springer Nature

For full activation of a T cell, this brake on negative immune modulation is necessary, but not sufficient. Another surface receptor, the T cell receptor (TCR), also needs to recognize and bind a ligand specifically derived from tumor cells and displayed on APCs. The full repertoire of antigens that activate antitumor T cells is only beginning to be discovered as new experimental approaches for profiling these ligands are emerging.

Computational approaches such as TraCeR (Nat. Methods 13, 329–332; 2016) were used to profile the diversity of full-length TCRs in T cells from single-cell RNA-seq data and were able to pair the reconstructed TCRs, including their antigen-binding sites, with the transcriptional profiles of the cells. This approach allowed the identification of clones specific for the same antigen. Experimental methods use baits to get a handle on TCR ligands. Christopher Garcia and colleagues, for example, used a library of peptide–human leukocyte antigens (pHLAs) displayed on yeast to screen orphan TCRs of tumor-infiltrating lymphocytes. The cognate pHLA bound TCRs with high specificity and allowed the identification of the antigen bound by the tumor-infiltrating T cells (Cell 172, 549–563; 2018).

To fully understand T cell activation and prevent unwanted negative modulation, scientists will need new wet and dry approaches to profile the receptors on a T cell and the ligands that engage them. The more cell-type-specific ligands we find that activate immune cells, the more likely it will be that receptors on T cells could be engineered to target specific cells. In a recent approach, directed by Yvonne Chan at UCLA, TCRs were engineered to respond to specific soluble ligands, instead of only surface-bound ones, which will broaden the repertoire of antigens a T cell is activated by (Nat. Chem. Biol. 14, 317–325; 2018).

The ultimate goal is to trigger cell killing only in response to specific ligands, while leaving the rest of the cells unscathed.