Breast Cancer Research volume 16, Article number: 457 (2014)
The emergence of molecular targeted therapies has revolutionized the clinical treatment of breast cancer. To guide treatment, patient samples are screened for expression of hormone receptors for estrogen and progesterone and the epidermal growth factor receptor HER2. Patients with tumors that do not express any of these three receptors (that is, triple-negative breast cancer) exhibit a worse outcome . Sequencing of cancer genomes suggests that over-expressing an oncogene or eliminating a tumor suppressor gene is also associated with passenger mutations. The presence of these passenger mutations may provide a collective signature that distinguishes malignant from normal cells. Conceptually, the adaptive immune system recognizes cells that present a different antigenic signature and provides a mechanism to control for malignant transformation. One approach to enhance anti-tumor immunity is to increase the number of T cells, either systemically, through inhibiting the action of CTLA-4, or locally, through inhibiting the programmed cell death 1 pathway. Therapeutic inhibition of these pathways is called immune checkpoint modulation . The clinical benefit received by a subset of patients with metastatic melanoma demonstrates proof-of-principle for this therapeutic approach .
In a retrospective study of invasive breast cancer, we found that increased expression of genes associated with type 1 immunity was a predictor of increased survival independent of molecular pathology . This gene signature includes type 1 T-cell polarization and enhanced cytotoxic T-cell and natural killer cell recruitment. While this finding is consistent with a number of other studies (for example, ), we also found that 70% of patients with invasive triple-negative breast cancer clustered with the cohort characterized by an increased type 1 immune signature. In examining the gene expression signature, we found that the expression of several type 1 immunity genes aligned along the direction of principal coordinate 1 (Figure 1A). In addition, expression of members of the programmed cell death 1 pathway (PDCD1 and CD274) that can be therapeutically targeted also aligned in the same direction (Figure 1B). Other genes typically associated with local immunosuppression, including TGFB1, MICB/MICA, HMGB1, HIF1A, FOXP3, and IL10, were not significantly different than random noise. Collectively, these findings suggest two points: first, patients with invasive triple-negative breast cancer have an increased propensity for on-going anti-tumor immunity; and second, therapeutic relief of the programmed cell death 1 pathway may improve overall survival in patients with triple-negative breast cancer.
DJK conceived the study, performed the bioinformatic analysis, analyzed the experimental data, and wrote the manuscript.
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This work was supported by grants from the National Science Foundation (CAREER 1053490) and the National Cancer Institute (NCI) R15CA123123. The content is solely the responsibility of the author and does not necessarily represent the official views of the NCI, the National Institutes of Health, or the National Science Foundation.
The author declares that he has no competing interests.
Below are the links to the authors’ original submitted files for images.
Klinke, D.J. Is immune checkpoint modulation a potential therapeutic option in triple negative breast cancer?. Breast Cancer Res 16, 457 (2014). https://doi.org/10.1186/s13058-014-0457-z