To develop a mouse model in which the tumor T cell repertoire can be temporally monitored in individual mice, Tsunoda and Aoki et al. showed that in mice bearing bilateral LLC tumors, the immune microenvironment, tumor growth, and T cell repertoires were similar on both sides, with the same tumor-reactive T cell clones infiltrating and expanding in both tumors. In bilateral lymph nodes, however, the frequency of overlapping clones was substantially lower, suggesting that tumor-reactive clones induced in the dLNs on each side differ, but equivalently mix during circulation and infiltrate into the bilateral tumors, where they proliferate in situ at the same rate.
Contributed by Lauren Hitchings
ABSTRACT: Temporal analysis of the T cell receptor (TCR) repertoire has been used to monitor treatment-induced changes in antigen-specific T cells in patients with cancer. However, the lack of experimental models that allow a temporal analysis of the TCR repertoire in the same individual in a homogeneous population limits the understanding of the causal relationship between changes in TCR repertoire and antitumor responses. A bilateral tumor model, where tumor cells were inoculated bilaterally into the backs of mice, could be used for temporal analysis of the TCR repertoire. This study examined the prerequisite for this strategy: the TCR repertoire is conserved between bilateral tumors that grow symmetrically. Bilateral tumors and draining lymph nodes (dLNs) were collected 13 days after tumor inoculation to analyze the TCR repertoire of CD4(+) and CD8(+) T cells. The tumor-infiltrating T-cell clones were highly similar between the bilateral tumors and expanded to a similar extent. In addition, the differences of TCR repertoire between the bilateral tumors were equivalent to Intra-tumoral heterogeneity on one side. On the other hand, the similarity of the TCR repertoire in the bilateral dLNs was markedly lower than that in the tumor, suggesting that tumor-reactive T cell clones induced independently in each dLN are mixed during recirculation and then proportionally infiltrated the bilateral tumors. These findings provide the basis for future analysis of temporal and treatment-induced changes in tumor-reactive T cell clones using this bilateral tumor model.