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JAK2 expression is associated with tumor-infiltrating lymphocytes and improved breast cancer outcomes: implications
Chris P Miller1, Jason D Thorpe, Amanda N Kortum
1Authors' Affiliations: Center for Computational Biology and Bioinformatics, Department of Electrical Engineering, Columbia University, New York, New York.
Abstract:
Janus kinase-2 (JAK2) supports breast cancer growth, and clinical trials testing JAK2 inhibitors are under way. In addition to the tumor epithelium, JAK2 is also expressed in other tissues including immune cells; whether the JAK2 mRNA levels in breast tumors correlate with outcomes has not been evaluated. Using a case-control design, JAK2 mRNA was measured in 223 archived breast tumors and associations with distant recurrence were evaluated by logistic regression. The frequency of correct pairwise comparisons of patient rankings based on JAK2 levels versus survival outcomes, the concordance index (CI), was evaluated using data from 2,460 patients in three cohorts. In the case-control study, increased JAK2 was associated with a decreasing risk of recurrence (multivariate P = 0.003, n = 223). Similarly, JAK2 was associated with a protective CI (<0.5) in the public cohorts: NETHERLANDS CI = 0.376, n = 295; METABRIC CI = 0.462, n = 1,981; OSLOVAL CI = 0.452, n = 184. Furthermore, JAK2 was strongly correlated with the favorable prognosis LYM metagene signature for infiltrating T cells (r = 0.5; P < 2 × 10(-16); n = 1,981) and with severe lymphocyte infiltration (P = 0.00003, n = 156). Moreover, the JAK1/2 inhibitor ruxolitinib potently inhibited the anti-CD3-dependent production of IFN-γ, a marker of the differentiation of Th cells along the tumor-inhibitory Th1 pathway. The potential for JAK2 inhibitors to interfere with the antitumor capacities of T cells should be evaluated.
Insights
Increased Janus kinase-2 (JAK2) mRNA in breast tumors correlates with a lower risk of recurrence and better outcomes. This suggests JAK2
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Janus kinase-2 (JAK2) is implicated in breast cancer progression.
- JAK2 is expressed in tumor cells and immune cells within the tumor microenvironment.
- The prognostic significance of JAK2 mRNA levels in breast tumors remains unevaluated.
Purpose of the Study:
- To investigate the association between JAK2 mRNA levels in breast tumors and patient outcomes.
- To determine if JAK2 mRNA levels correlate with distant recurrence risk.
- To explore the relationship between JAK2 expression and immune cell infiltration.
Main Methods:
- A case-control study measured JAK2 mRNA in 223 breast tumors.
- Logistic regression analyzed associations with distant recurrence.
- Concordance index (CI) evaluated JAK2 levels against survival in 2,460 patients across three cohorts.
- Correlation analysis assessed JAK2 mRNA with the LYM metagene signature and lymphocyte infiltration.
- In vitro experiments tested the effect of JAK1/2 inhibitor ruxolitinib on IFN-γ production.
Main Results:
- Higher JAK2 mRNA levels were significantly associated with a decreased risk of recurrence (multivariate P = 0.003).
- JAK2 mRNA showed a protective CI (<0.5) across three independent cohorts (NETHERLANDS CI = 0.376, METABRIC CI = 0.462, OSLOVAL CI = 0.452).
- JAK2 expression strongly correlated with favorable prognosis markers: LYM metagene signature (r = 0.5, P < 2 × 10(-16)) and severe lymphocyte infiltration (P = 0.00003).
- Ruxolitinib inhibited IFN-γ production, a marker of tumor-inhibitory T cell differentiation.
Conclusions:
- Elevated JAK2 mRNA levels in breast tumors are a favorable prognostic indicator, associated with reduced recurrence risk.
- JAK2 expression correlates with a robust anti-tumor immune response, specifically T cell infiltration.
- The findings suggest a complex role for JAK2 in breast cancer immunity and warrant evaluation of JAK2 inhibitors' impact on anti-tumor immunity.
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