Imaging and Defining Emergent Behaviors of the Immune Response

Curing Cancer through Immunity

History of Checkpoint Blockade.

As a graduate student, I made antibodies against the then-unknown molecule CTLA-4, demonstrated that these could either deliver or block inhibitory signals to T cells and determined that those antibodies could be used to augment T cell responses in vaccination, in responses to super-antigens and multiple other model systems. This checkpoint blockade quickly became best-known for augmenting T cell response to tumors. Our method (Krummel, Leach, Allison) became the first patent for Checkpoint immunotherapy and is the science underlying Yervoy, the first approved Immunotherapy drug.

The Next Generation

Using live-imaging, we found that T cells in the tumor microenvironment were being ‘captured’ into non-stimulatory synapses by what turned out to be macrophages (Engelhardt et al. Cancer Cell 2012).  In Broz et al Cancer Cell 2014, we dissected the entire myeloid lineage to show that there is subset of tumor-resident CD103+ DC that oppose macrophages, provided genetic signatures that define each cell type, and showed that patients with higher numbers of those kinds of DC live longer, without treatment.  In Roberts et al Cancer Cell 2016, we further showed how those cells are critical in delivering tumor antigens to lymph nodes where they further disseminate that antigen to other dendritic cells and activate T cells. In Headley et al Nature 2016, we showed how the same opposition of macrophages versus DC was critical in determining metastatic success. We are very actively seeking to understand how to modulate the balance of these cells to complement checkpoint blockade.

Krummel Lab © 2019