Adoptive cell therapy of cancer using self-specific memory phenotype CD8+ T cells

Could an unconventional type of “killer” T-cell be the answer to making immunotherapy more effective?

The advent of immunotherapy has provided a new weapon in the fight against cancer. Yet to date, only a minor fraction of cancer patients show benefit from immunotherapy, demonstrating that innovative new strategies are needed. CD8+ “killer” T cells play a leading role in anti-tumor immune response due to their capacity to selectively kill tumor cells when they specifically recognize particular short peptide antigens displayed on the tumor cell surface. In some cancers, CD8+ T cells can also recognize “neo-antigen” peptides encoded by mutated genes within the cancer genome. Targeting these neo-antigen peptides is an attractive strategy for immunotherapy, because mutated neo-antigens are specifically displayed by tumor cells, and not by normal cells. However, efforts to harness neo-antigen-specific T cells for cancer therapy have been stymied because many cancers have a very low density of mutations, and thus are likely to have few neo-antigens to attract these particular T cells.

Recently, Dr. Savage led a research team that made an unexpected discovery: mouse prostate tumors recruit a distinct class of identifiable CD8+ T cells called “memory-phenotype” CD8+ T cells (CD8-MP cells), which had been largely overlooked in the tumor immunology field. These cells account for 5-10% of all the CD8+ T cells in healthy mice and show signs of prior antigen encounter.  Dr. Savage’s group showed that these T-cells can be triggered by self-antigen peptides early in their development, and then spread through the body, ready to be recruited into immune responses.  Further, these “memory phenotype” T cells are readily recruited into mouse prostrate tumors and express high levels of PD-1, an inhibitory receptor which has already been effectively leveraged by therapeutic blocking antibodies. Lastly, experiments revealed that only certain CD8-MP cells are drawn into the mouse tumors, suggesting that these cells are drawn in by a limited set of self-peptides.

These discoveries raise the intriguing possibility that self-peptide specific CD8-MP cells could be leveraged for the treatment of cancer. Indeed, since CD8-MP cells recognize non-mutated self-peptides, cell therapy using tumor-associated CD8-MP clones may allow a “one size fits all” approach for cancer therapy, because the self-peptides targeted by CD8-MP cells may be found in multiple cancer types and could be similar in many cancer patients. Dr. Savage will use his Fletcher Scholars Award to perform proof-of-principle studies to define the efficacy of adoptive T cell therapy by using select CD8-MP clones to trigger anti-tumor immunity in a mouse model of oncogene-driven prostate cancer. Therapies using expanded CD8-MP clones may be able to drive tumor regression by directly killing tumor cells, or by inducing the destruction of the normal stromal cells that support tumor growth. Our hope is that these studies will provide the experimental and conceptual foundation for innovative new cancer therapies that leverage memory-phenotype CD8+ T cell clones.

Peter A. Savage is an Associate Professor in the Department of Pathology at the University of Chicago.  He was awarded the Cancer Research Foundation Young Investigator Award in 2009.  More about Dr. Savage and his work can be found here:  https://voices.uchicago.edu/savagelab/