Reprogramming T cell specific immune responses to Cyclin B1 in breast cancer patients using a TLR 8/7 agonist.

Abstract

Cyclin B1 is a cell cycle regulatory protein aberrantly overexpressed in a number of cancers, including breast cancer. While the current standards of care for breast cancer are sometimes curative, many patients suffer relapse. This necessitates novel therapeutic approaches. Therapeutic vaccination has become an increasingly attractive option because of the ability to expand and possibly correct the function of cancer antigen-specific T cells, expand memory T cells, and effectively control tumor antigen delivery. Therefore, we analyzed the immune repertoire to Cyclin B1 in patients with breast cancer in order to achieve these goals. Healthy donor CD4+ and CD8+ T cells can express IFNγ in response to Cyclin B1 long peptides, thus confirming prior findings. Cyclin B1 long peptides were also able to stimulate antigen-specific cytokine secretion from breast cancer patients PBMCs (22 out of 25 patients studied). However, PBMCs from breast cancer patients secrete high amounts of type 2 cytokines (IL-4, IL-5, IL-13, TNFα) and low amounts of IFNγ when compared to healthy donors. These results suggest a Type 2 bias in breast cancer patients PBMCs, similar to our earlier findings showing a pro-tumor, inflammatory Th2 microenvironment in tumor infiltrates. We next analyzed whether this response could be modified, resulting in a block of Th2 cytokines, or increase in Th1 cytokines. Our earlier studies suggested that CL-075, a TLR8/7 agonist, generates Type I cytokine secretion and drives antigen-specific CD8+ T cell responses. In healthy donor PBMCs, we found this led to a significant increase in the amount of antigen-specific IFNγ expressed by both CD4+ and CD8+ T cells. In breast cancer patient PBMCs, 21 out of 22 patients showed a modified cytokine secretion signature that was antigen-specific with CL-075. Those patients were also able to either increase IFNγ-specific response or block Th2 cytokine response, while 6 out of 22 patients were able to do both. Therefore, the inflammatory Th2 immune response to Cyclin B1 in breast cancer patients can be modified using a TLR8/7 agonist, thereby providing a rationale for a combination of Cyclin B1 long peptides and TLR8/7 agonists as a therapeutic possibility.