JAK2 expression is associated with tumor-infiltrating lymphocytes and improved breast cancer outcomes: implications for evaluating JAK2 inhibitors.
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.
Authors' Affiliations: Center for Computational Biology and Bioinformatics, Department of Electrical Engineering, Columbia University, New York, New York.
Chris P
CP
Miller
Jason D
JD
Thorpe
Amanda N
AN
Kortum
Catherine M
CM
Coy
Wei-Yi
WY
Cheng
Tai-Hsien
TH
Ou Yang
Dimitris
D
Anastassiou
J David
JD
Beatty
Nicole D
ND
Urban
C Anthony
CA
Blau
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D012008:Recurrence; D016896:Treatment Outcome
D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D053614:Janus Kinase 2