TCR Repertoires of Tumor Infiltrating T Cells in Metastatic Breast Cancer

Breast cancer is the most prevalent cancer in women around the world, accounting for 30% of all new cancer cases in women in the US. In this study, we examine genetic and immunological data from eight breast cancer patients who had died from metastatic breast cancer, focusing on the T cell response to the metastases. This response is mediated by tumor infiltrating lymphocytes (TILs). We capture a sample of the T cell repertoire in the metastases by sequencing the alpha and beta chains of T cell receptors, found on TILs inside the different metastases, using high-throughput sequencing (TCRSeq).

We start by studying classic notions of TCR repertoires like sharing and expansion and show the role they play in shaping the metastatic repertoire. Next, by using unsupervised learning techniques we are able to show that the T cell response has a distinct organ specific signature, i.e., it is more similar in metastases in the same organ than in metastases in different organs. We also show that there is a high correlation between the organization of the T cell response, and the mutational landscape of breast cancer as captured by a phylogenetic model of the evolution of patient’s metastases.

This work has interesting consequences for designing new T cell based immune-therapies. Especially, it shows that any therapy of this kind should take into account the different immune signature of metastases in different organs.

These findings were published recently (May 2019) in Cell Reports: "The genomic and immune landscapes of lethal metastatic breast cancer"