Abstract
BackgroundIn prostate cancer, genes encoding androgen-regulated, Y-chromosome-encoded, and tissue-specific antigens may all be overexpressed. In the adult male host, however, most high affinity T cells targeting these potential tumor rejection antigens will be removed during negative selection. In contrast, the female mature T-cell repertoire should contain abundant precursors capable of recognizing these classes of prostate cancer antigens and mediating effective anti-tumor immune responses.Methodology/Principal FindingsWe find that syngeneic TRAMP-C2 prostatic adenocarcinoma cells are spontaneously rejected in female hosts. Adoptive transfer of naïve female lymphocytes to irradiated male hosts bearing pre-implanted TRAMP-C2 tumor cells slows tumor growth and mediates tumor rejection in some animals. The success of this adoptive transfer was dependent on the transfer of female CD4 T cells and independent of the presence of CD25-expressing regulatory T cells in the transferred lymphocytes. We identify in female CD4 T cells stimulated with TRAMP-C2 a dominant MHC II-restricted response to the Y-chromosome antigen DBY. Furthermore, CD8 T cell responses in female lymphocytes to the immunodominant MHC I-restricted antigen SPAS-1 are markedly increased compared to male mice. Finally, we find no exacerbation of graft-versus-host disease in either syngeneic or minor-antigen mismatched allogeneic lymphocyte adoptive transfer models by using female into male versus male into male cells.Conclusions/SignificanceThis study shows that adoptively transferred female lymphocytes, particularly CD4 T cells, can control the outgrowth of pre-implanted prostatic adenocarcinoma cells. This approach does not significantly worsen graft-versus-host responses suggesting it may be viable in the clinic. Further, enhancing the available immune repertoire with female-derived T cells may provide an excellent pool of prostate cancer reactive T cells for further augmentation by combination with either vaccination or immune regulatory blockade strategies.
Highlights
Despite improvements in detection and treatment, prostate cancer (CaP) remains the second leading cause of cancer death in men in the United States and the second most common cancer in men worldwide
We report that adoptively transferred naıve female lymphocytes slow the growth of and, in some cases, reject preimplanted transgenic adenocarcinoma of mouse prostate (TRAMP)-C2 prostatic adenocarcinoma cells in sublethally irradiated male mice
They identified T cells as mediators of anti-prostate cancer immune responses in female mice and found that adoptive transfer of vaccinated female lymphocytes can lead to control of growth of TRAMP-C2 tumors in male hosts
Summary
Despite improvements in detection and treatment, prostate cancer (CaP) remains the second leading cause of cancer death in men in the United States and the second most common cancer in men worldwide. Sipuleucel-T, a vaccine designed to elicit an immune response against prostatic acid phosphatase, was shown to improve median survival of patients with metastatic castrationresistant CaP [1]. Blockade of the immune regulatory molecule CTLA-4 has shown clinical promise for prostate cancer [2,3]. Development of immunotherapeutic interventions which target multiple aspects of the immune system in CaP may offer greater clinical benefit and more durable responses. Development of immunotherapeutic interventions which target multiple antigens in CaP may offer greater clinical benefit and more durable responses. The female mature T-cell repertoire should contain abundant precursors capable of recognizing these classes of prostate cancer antigens and mediating effective anti-tumor immune responses
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