Research Suggests Leveraging αβ T Cell Receptor Mechanobiology Could Improve Cancer Therapy

New advances in scientists’ understanding of αβ T cell receptor (TCR) mechanobiology could have a major impact on the treatment of various types of cancer, according to a new report.

The article, published in PNAS, argues that the application of the new mechanobiological knowledge to the field of oncology could result in better cancer vaccines and immunotherapies.

Corresponding author Matthew J. Lang, PhD, of the Vanderbilt University School of Medicine, and colleagues, said some cancer types, such as melanomas and a minority of non-small cell lung cancers (NSCLC) are susceptible to checkpoint blockade therapy (CB), because they display myriad tumor-specific neoantigens that prompt an immune response. Cytolytic T lymphocytes (CTLs) are generated against such neoantigens, mediating the destruction of aberrant cells.

“However, for many other forms of cancer, including the remaining 80% of NSCLCs, almost all ovarian cancers, and brain cancers, to mention a few, the paucity of neoantigens arrayed on the tumor cell prevents the immune system from effectively generating CTLs in the first instance,” Lang and colleagues wrote. “Unsurprisingly, no positive response is engendered by CB.”

While other strategies, such as chimeric antigen receptor T-cell therapy, have been developed to overcome these challenges, the authors said they generally come with high costs and their benefits may be transient.

However, the authors said the field of immunotherapy has not yet exploited recent advances in scientists’ understanding of “fundamental T cell receptor (TCR) structural biology and antigen-specific cognate recognition of the αβ T cell lineage.”

They explained that directing TCRs with digital performance characteristics—meaning they require only one or a few countable ligands for activation—at physically detected neoantigens could lead to dramatic steps forward for cancer vaccines and immunotherapies, because they can target tumors with both sparsely and luminously arrayed tumor-associated antigens (TAAs).

The authors argue that a better understanding of αβTCR evolution could make it easier for investigators to develop better therapeutic options for patients with difficult to treat cancers, including options that avoid the autoimmune inflammatory toxicities often seen in checkpoint blockade therapy.

In their piece, Lang and colleagues lay out the latest findings related to the features of αβTCRs, including its mechanosensing features, and how those characteristics might translate into optimized T cell monitoring and immunotherapy.

“The matching of TCR mechanosensory performance with distinct neoantigen displays is likely to create a new dawn of immuno-oncology for personalized immunotherapies including targeting of certain high-value truncal neoantigens such as TP53 shared by multiple patients,” the authors said.

The investigators noted that TAAs are not tumor-specific peptides, since they can be expressed on normal cells, but they added that “the array of certain TAA across tissues and cell types can be very limited in distribution while highly overexpressed on tumors. This differential expression profile creates a therapeutic opportunity.”

Lang and colleagues wrote that the opportunity also exists to avoid cross-reactivity against off-target antigens, though they said such a goal can only be achieved with a nuanced appreciation of TCR mechanobiology.

Ultimately, the investigators said a careful application of mechanobiological insights could yield meaningful therapeutic developments across cancer types.

“We assert that TCRs with digital ligand-sensing performance capability directed at sparsely as well as luminously displayed tumor-specific neoantigens and certain tumor-associated antigens can improve effective cancer vaccine development and immunotherapy paradigms,” they concluded.

Reference

Reinherz EL, Hwang W, Lang MJ. Harnessing αβ T cell receptor mechanobiology to achieve the promise of immuno-oncology. Proc Natl Acad Sci USA. 2023;120(27):e2215694120. doi:10.1073/pnas.2215694120