Healthy individuals have T-cell and antibody responses to the tumor antigen cyclin B1 that when elicited in mice protect from cancer

Abstract

We previously identified the aberrantly expressed cell cycle regulator cyclin B1 as a tumor antigen recognized by antibodies and T cells from patients with breast, lung, and head and neck cancers. Ordinarily expressed only transiently in the G2/M stage of the cell cycle in normal cells, cyclin B1 is constitutively expressed at high levels in the cytoplasm of these and many other tumor types, leading to its recognition by the cancer patient's immune system. We report here an unexpected observation that cyclin B1-specific antibody and memory CD4 and CD8 T cells are also found in many healthy individuals who have no history of cancer. Moreover, young as well as older healthy people have these responses suggesting that events other than cancer, which occur either early in life or throughout life, may lead to aberrant cyclin B1 expression and anti-cyclin B1 immunity. The role, if any, of immunity to this tumor-associated antigen is not known. We wanted to determine specifically whether immunity to cyclin B1 might be important in the immunosurveillance of cyclin B1؉ tumors. We therefore tested in mice the effectiveness of vaccine-elicited anticyclin B1 immunity against a cyclin B1؉ mouse tumor that was chosen based on our published observation that cyclin B1 overexpression is associated with the lack of p53 function. We found that cyclin B1 DNA prime-protein boost vaccine protected mice from a challenge with a tumor cell line that was established from a tumor arising in the p53 ؊/؊ mouse that spontaneously overexpresses cyclin B1.cancer vaccines ͉ human immunology ͉ immunosurveillance ͉ tumor immunology O verexpression of cyclin B1 has been documented in many human cancers, including colorectal, lung, cervical, and head and neck carcinomas (1-5). Additionally, this overexpression has been shown to correlate with worse prognosis in lung, laryngeal, esophageal, and tongue cancers (1,3,(5)(6)(7)(8). Whereas cyclin B1 is expressed transiently in normal cells, in cancer cells, it is expressed constitutively in all stages of the cell cycle (9). Additionally, cancer-associated cyclin B1 overexpression is evident primarily in the cytoplasm where it can be subject to proteasomal processing and presentation in MHC class I. We reported isolation of cyclin B1 peptides from MHC class I molecules of tumor cells that were recognized by tumor-specific memory T cells present in patients with cyclin B1 overexpressing tumors (10). We later showed that patients with cancer and premalignant lesions that overexpress cyclin B1 have cyclin B1-specific antibodies of IgM, IgG and IgA isotypes (11).Cyclin B1 overexpression in many tumors is secondary to the loss of p53 function either through p53 mutations or a deletion (9). Considering that alterations in p53 function happen in many tumors early in the process of transformation, cyclin B1 is a good candidate antigen for both immunotherapy and immunoprevention of a large number of human tumors. Additionally, because cyclin B1 is required for entry into mitosis, it is unlikely that a growing tum...

The Tumor Antigen Cyclin B1 Hosts Multiple CD4 T Cell Epitopes Differently Recognized by Pre-Existing Naive and Memory Cells in Both Healthy and Cancer Donors

“…We also confirmed the spontaneous CCNB1-specific IgG response observed in healthy and cancer patients (30,31,(53)(54)(55)). We observed a similar level of anti-CCNB1 Abs in patients and healthy donors (31).…”

“…The four healthy donors respond mainly to six peptides, namely 199-216, 207-221, 212-226, 221-235, 225-239, and 241-258. This is clearly reminiscent of a previous study showing that five healthy donors reacted in similar short-term T cell assays to three overlapping peptides (215-229, 219-233, and 223-234) (30). We therefore extended the sequence containing the previously identified peptides (30) with peptides located on both sides of it.…”

“…These CCNB1-specific T cells recognized a limited set of very good binders to HLA class II molecules and were found in both healthy and cancer donors. As proposed by Vella et al (30), CCNB1-specific memory T cells could have been primed by endogenous CCNB1 after alteration of its expression in the periphery. Infection by CMV (47) or varicella zoster virus (48) has been shown to induce overexpression of CCNB1 in infected cells and may favor initiation of the T cell response.…”

“…Overexpression has been observed in several human solid tumors, including breast (23), lung (24), colon (25), prostate (26), and head and neck (26) cancers. Tumor-specific CTL response raised against CCNB1 has already been observed in healthy donors and cancer patients (27)(28)(29), whereas the CD4 response specific to CCNB1 has scarcely been investigated and only in healthy donors (30). Strikingly, it has also been observed that CCNB1-specific Abs pre-exist in healthy donors (30,31).…”

“…Tumor-specific CTL response raised against CCNB1 has already been observed in healthy donors and cancer patients (27)(28)(29), whereas the CD4 response specific to CCNB1 has scarcely been investigated and only in healthy donors (30). Strikingly, it has also been observed that CCNB1-specific Abs pre-exist in healthy donors (30,31). Because CCNB1 is widely expressed in malignancies and is not dispensable for tumor cells, we evaluated a part of its vaccine potential by performing a comprehensive analysis of the CD4 T cell response specific to CCNB1 in healthy and cancer patients.…”