Description

Pre-Existing Immune Memory in Healthy Donors to Cancer-Associated Phosphopeptides

Amanda Lulu, MS,¹ Kara Cummings, PhD,¹ Victor Engelhard, PhD¹

¹University of Virginia, Beirne B. Carter Immunology Center

Identifying appropriate antigens are key to developing effective immune therapies for cancer. Dysregulated signaling is a hallmark of cancer cells, with phosphorylated proteins playing major roles as signal transducers in pathways contributing to the malignant phenotype. Our lab has identified Major Histocompatibility Complex Class-I presented phosphopeptides as a new class of cancer-associated neoantigens. The source proteins of many phosphopeptides contribute to malignant phenotypes in different cancer types. We previously reported that 10 healthy donors who had no evident prior cancer have unusually robust CD8 T cell responses to a cohort of HLA-B7⁺ leukemia-associated phosphopeptides. Some of the responses were comparable to responses to Influenza, suggesting that they represented memory T cells. To test this directly, we evaluated responses in CD8⁺CD45RO⁺ memory T cells purified from the blood of healthy donors. These cells showed robust responses to 0-19% of HLA-A2⁺ and 0-23% of HLA-B7⁺ cancer-associated phosphopeptides. This demonstrates that healthy individuals with no evident cancer history have pre-existing immune memory to some cancer-associated phosphopeptides. Interestingly, phosphopeptides are more likely to be targets of immune memory if they are associated with multiple cancer types. Additionally, many of the memory targets are shared by multiple donors. These data suggest that healthy individuals develop pre-existing immune memory to cancer-associated phosphopeptides due to immune surveillance of incipient cancer cells. It also suggests that more common transformation related processes lead to broad based exposure in multiple individuals. Future work will elucidate the molecular epidemiology of cancer-associated phosphopeptides that are targets of pre-existing immune memory in healthy donors.

Funding: NIH/NCI R01 CA190665; UVA Peach Fellowship; NIH/NCI Cancer Training Grant T32 CA009109