Dissecting Antigen-Specific T-Cell Immunity in Human Cancer and Acquired Resistance to Immunotherapy

T lymphocytes are at the very center of the rapidly expanding universe of cancer immunotherapy. We now know that each T cell clonotype can in fact contain a stem cell-like system, which is capable of self-renewal and differentiation. We have described the identification of human T memory stem cells (TSCM). TSCM maintain robust replicative capacity and are multipotent in their ability to give rise to cytolytic effector and memory progeny. Stem-cell-like T cells are epigenetically distinct. From their poised epigenetic and metabolic states, TSCM efficiently can give rise to cells with a multiplicity of identities required for successful immune responses, and collectively provide protection against infections and cancer.

We have visualized the chromatin states of TSCM on a whole genome level. We have found that the transcription factor Bach2 is a repressor of T cell receptor-driven programs. These findings go a long way in identifying a molecular mechanism that enables T cells to maintain their stem cell-like state. We have direct evidence that sufficient T cell activation can overwhelm the repressive influence of Bach2 through the action of the Akt kinase. Akt mediates the core events of T cell differentiation and it is possible to selectively block the Akt pathway with an allosteric inhibitor enabling the creation of long-lived, less-differentiated T cells that are much more effective therapeutically in a mouse model of established tumor. These findings form the basis for a novel immunometabolomic approach to improve cell-intrinsic features of therapeutic T cells in the clinic.

Finally, we will describe how even the most effective T cells can be thwarted by mechanisms in place in the tumor microenvironment. Our recent and unpublished findings involve two elements from the periodic table - potassium and oxygen - that can be immunosuppressive under certain physiologic conditions. We have also described an internal T cell checkpoint mechanism called Cish. We furthermore seek to find ways of overcoming the powerful physiology that can enable tumors to grow and kill their hosts. These efforts can produce T cells that are capable of increased anti-tumor efficacy.