Contraction of T cell richness in lung cancer brain metastases

Abstract

Very little is known about how the adaptive immune system responds to clonal evolution and tumor heterogeneity in non-small cell lung cancer. We profiled the T-cell receptor β complementarity determining region 3 in 20 patients with fully resected non-small cell lung cancer primary lesions and paired brain metastases. We characterized the richness, abundance and overlap of T cell clones between pairs, in addition to the tumor mutation burden and predicted neoantigens. We found a significant contraction in the number of unique T cell clones in brain metastases compared to paired primary cancers. The vast majority of T cell clones were specific to a single lesion, and there was minimal overlap in T cell clones between paired lesions. Despite the contraction in the number of T cell clones, brain metastases had higher non-synonymous mutation burdens than primary lesions. Our results suggest that there is greater richness of T cell clones in primary lung cancers than their paired metastases despite the higher mutation burden observed in metastatic lesions. These results may have implications for immunotherapy.

Figure 1

Comparative T cell richness and overlap. Each bar represents the detected T cell clones in one subject’s paired specimens. The unique T cell clones in the primary lesions are shown in red, the unique T cell clones in the brain metastasis are shown in blue, and the overlapping clones are in purple.

Figure 2

Clonal distributions. Unique T cell clones are plotted by the number of tumors (x axis) in which they were identified. (A) The vast majority of clones were only observed in one tumor. The relative fraction of the top ten clones (black bars) is plotted against the total number of T cells (gray bars) in matched pairs of lung tumors [L] and brain metastases [B] for all 20 cases (B).

Figure 3

Hive plot of T cell clonality, tumor mutation burden and neoantigen prediction. The number of unique, productive T cell clones (TCR), the tumor mutation burden (TMB) and the predicted neoantigen load (NeoAg) for primary lung cancers (blue lines) and brain metastases (white lines) are plotted along each axis of this hive plot. The central point represents a value of zero for all axes. The axes have been normalized such that the ends represent the highest value for that measurement.