Reeves Lab areas of interest:
Tumor heterogeneity & spatial organization of the anti-tumor immune response
Consequences of Neoantigen heterogeneity on the T cell response
Tumor evolution following immunotherapy
Tumor Heterogeneity: Some Background
As tumors grow, they also evolve and become heterogeneous. 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.
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.
We are interested in the dynamics of the immune response to heterogeneous tumors. We have established a novel platform to model tumor heterogeneity, making use of >60 cell lines we have established from carcinogen-induced skin squamous cell carcinomas (SCCs). These cell lines carry a high but physiologically relevant mutation burden, and exhibit a range of reproducible immune infiltrates when implanted in mice. We have introduced fluorescent tags into these cell lines, enabling us to mix them and implant mice with reproducible heterogeneous tumors in which constituent populations can be precisely tracked and individually modulated.
We have shown that in a tumor comprised of immunologically “hot” and “cold” populations (see figure below), heterogeneous tumors are a patchwork of “hot” and “cold” tumor cells and T cells preferentially accumulate in “hot” regions.
Building on this platform, some current questions we are asking are:
What molecular mechanisms control the spatial organization of immune cells in heterogeneous tumors?
How does a heterogeneous tumor evolve after treatment with immunotherapy? Can immunotherapy productively alter “bad” patterns spatial organization of T cells in heterogeneous tumors?
How does tumor composition, i.e., ratio of “hot” to “cold” tumor cells, influence the overall anti-tumor immune response and the spatial organization of immune cells?
What rules govern how the immune system will respond to a heterogeneous (e.g., subclonal) tumor antigen?
Cross-section of a tumor comprised of a 1:1 mixture of “hot” (YFP) and “cold” (RFP) tumor cells. Analysis of T cells in these 1:1 mixed tumors reveal that T cells preferentially localize to the “hot” (YFP) regions and show better effector function in these regions as well.