Reeves Lab areas of interest:

  • Tumor heterogeneity & evolution

  • Impact of tumor heterogeneity on the immune response

  • Heterogeneity in tumor-responding T cell clones

Tumor Heterogeneity & Evolution

As tumors grow, they also evolve. Tumor evolution has been likened to Darwin's evolution of species. While tumors, in most cases, originate from a single mutant cell, as they grow, daughter cells will acquire additional mutations. As these daughter cells expand with their new mutations, the result is a tumor which is a patchwork of different populations—a genetically heterogeneous tumor, with different regions of tumor carrying distinct mutations.

Tumor Evolution fig 4-01.jpg

We are interested in the patterns of heterogeneity that arise during tumor progression and metastasis, and the behavior of distinct tumor clones that are growing side-by-side. We use multi-color Confetti fluorescent lineage tracing in combination with sequencing to study tumor clones and their properties. Some questions we are specifically interested in are:

  • How do clones in a malignant tumor interact? Do they exhibit cooperative, competitive, or stochastic dynamics?
  • Does clonal behavior differ between primary and malignant tumors? How much of the clonal diversity observed in a primary tumor is carried to its respective metastases?

Impact of TUMOR HETEROGENEITY on the Immune Response

An effective anti-tumor immune response is in most cases dependent on the ability of T cells to recognize and attack tumor cells. T cells can identify tumor cells by recognizing tumor neo-antigens, which are the result of mutations in the tumor cell. However, tumor neo-antigens display the same spatial and clonal heterogeneity that mutations do, making tumors a complex target.

Heterogeneous neoantigens fig 2-01.jpg

We are interested in the dynamics of the adaptive immune response to heterogeneous tumors. We use both carcinogen-induced tumors, which naturally evolve heterogeneous patterns, and engineered models of tumor heterogeneity to study these dynamics. Some of the questions we are interested in asking are:

  • How does spatial heterogeneity—of tumor mutations, and more generally of tumor clones—affect the immune cell infiltrate in a tumor?
  • What rules govern how the immune system will respond to a subclonal neo-antigen? When can a subclonal neo-antigen potentiate tumor clearance vs. immunoediting and tumor resistance?

Heterogeneity in tumor-responding T cell clones

The T cell repertoire is comprised of billions of distinct T cell receptors (TCRs), and tumors can carry hundreds to thousands of potential neo-antigens. Nonetheless, analysis of effect immune-based tumor rejections has suggested that a small number of tumor-responsive T cell clones dominate the anti-tumor response. We are interested in using the same tools we've applied to study tumor heterogeneity—Confetti labeling and sequencing—to investigate the dynamics and spatial organization in the tumor of individual responding T cell clones.