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Review
. 2021 May 26;13(11):2611.
doi: 10.3390/cancers13112611.

Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors-A Strategy for Hematological Malignancies?

Klara Klein  1 , Dagmar Stoiber  2 , Veronika Sexl  1 , Agnieszka Witalisz-Siepracka  1   2
Affiliations
Review

Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors-A Strategy for Hematological Malignancies?

Klara Klein et al. Cancers (Basel). .

Abstract

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway propagates signals from a variety of cytokines, contributing to cellular responses in health and disease. Gain of function mutations in JAKs or STATs are associated with malignancies, with JAK2V617F being the main driver mutation in myeloproliferative neoplasms (MPN). Therefore, inhibition of this pathway is an attractive therapeutic strategy for different types of cancer. Numerous JAK inhibitors (JAKinibs) have entered clinical trials, including the JAK1/2 inhibitor Ruxolitinib approved for the treatment of MPN. Importantly, loss of function mutations in JAK-STAT members are a cause of immune suppression or deficiencies. MPN patients undergoing Ruxolitinib treatment are more susceptible to infections and secondary malignancies. This highlights the suppressive effects of JAKinibs on immune responses, which renders them successful in the treatment of autoimmune diseases but potentially detrimental for cancer patients. Here, we review the current knowledge on the effects of JAKinibs on immune cells in the context of hematological malignancies. Furthermore, we discuss the potential use of JAKinibs for the treatment of diseases in which lymphocytes are the source of malignancies. In summary, this review underlines the necessity of a robust immune profiling to provide the best benefit for JAKinib-treated patients.

Keywords: JAK; JAK inhibitor; NK cells; STAT; T cells; leukemia.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic view of anti-tumor and immunosuppressive effects of JAKinibs downstream of JAK2/JAK2 and JAK1/JAK3-dependent pathways. Left side: In a physiological situation, EPO (erythropoietin) and TPO (thrombopoietin) signal via JAK2/JAK2 pairs to induce erythro-/thrombopoiesis (right side of the receptor). In a cancerous situation (indicated by formula image), the same signaling pathway drives MPNs (myeloproliferative neoplasms; left side of the receptor). Right side: In a physiological situation, common gamma chain-dependent cytokines (e.g., IL-2/7/15) signal via JAK1/JAK3 pairs to induce lymphopoiesis and regulate T/B/NK-cell function (right side of the receptor). In a cancerous situation (indicated by formula image), the same signaling pathway drives leukemias and lymphomas originating from T/B/NK cells (left side of the receptor). The consequences of JAKinib treatment on physiological and pathological effects of the pathways are indicated by colors (see legend).
See this image and copyright information in PMC

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