Longitudinal T cell receptor repertoire analysis in immunotherapy of HER2-positive breast cancer

Breast cancer is the most common malignant disease in women. Certain subtypes of breast cancer, like HER2-positive breast cancer overexpressing the receptor HER2, are treated using neoadjuvant immunochemotherapy containing anti-HER2 antibodies.

T cells are immune cells identified by a T cell receptor, which is capable of highly specific binding to antigenic peptides presented by major histocompatibility complex proteins, and which arises from somatic recombination of genes in the T cell receptor locus.

To better understand the role of T cells in the mechanism of action of anti-HER2 drugs, to improve our understanding of anti-breast cancer immunity in general, as well as to identify potential new biomarkers of breast cancer, we performed high-throughput peripheral-blood T cell receptor sequencing on 19 breast cancer patients (11 with HER2-positive and 8 with triple-negative breast cancer) undergoing neoadjuvant immunochemotherapy, with 10 timepoints sampled per patient.

We found that HER2-positive breast cancer patients showed generally reduced T cell receptor repertoire diversity compared to triple-negative breast cancer patients, and that in the HER2-positive group only, diversity tended to fall over the course of neoadjuvant therapy. We also found that the repertoires of HER2-positive breast cancer patients showed increased usage of T cell receptor genes associated with mucosal-associated invariant T (MAIT) cells, a semi-invariant subtype of T cells capable of recogizing certain small-molecule bacterial metabolites. Finally, we identified individual T cell clonotypes that were shared between multiple patients and showed differential expression over the course of neoadjuvant therapy.

Our results confirm the dual role of repertoire diversity in an effective antitumor immune response, while suggesting that this effect may be more relevant in HER2-positive breast cancer compared to triple-negative breast cancer. Conversely, our results suggest that in triple-negative breast cancer, MAIT cells may play a particularly important role in antitumor immunity. The clonotypes we found to have shared differential expression among multiple patients may serve as a basis for future classification models for early diagnosis and subtyping of breast cancer.