- Open Access
Is immune checkpoint modulation a potential therapeutic option in triple negative breast cancer?
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.
Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA: Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007, 13: 4429-4434. 10.1158/1078-0432.CCR-06-3045.
Topalian SL, Drake CG, Pardoll DM: Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012, 24: 207-212. 10.1016/j.coi.2011.12.009.
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010, 363: 711-723. 10.1056/NEJMoa1003466.
Klinke DJ: Induction of Wnt-inducible signaling protein-1 correlates with invasive breast cancer oncogenesis and reduced type 1 cell-mediated cytotoxic immunity: a retrospective study. PLoS Comput Biol. 2014, 10: e1003409-10.1371/journal.pcbi.1003409.
Schalper KA, Velcheti V, Carvajal D, Wimberly H, Brown J, Pusztai L, Rimm DL: In situ Tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res. 2014, 20: 2773-2782. 10.1158/1078-0432.CCR-13-2702.
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.
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.
About this article
Cite this article
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
- Breast Cancer
- Epidermal Growth Factor Receptor
- Natural Killer Cell
- Programme Cell Death