Regulation of bone homeostasis by MERTK and TYRO3.

The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect. Consequently, pharmacologic MERTK blockade by the small molecule inhibitor R992 increases osteoblast numbers and bone formation in mice. Furthermore, R992 counteracts cancer-induced bone loss, reduces bone metastasis and prolongs survival in preclinical models of multiple myeloma, breast- and lung cancer. In summary, MERTK and TYRO3 represent potent regulators of bone homeostasis with cell-type specific functions and MERTK blockade represents an osteoanabolic therapy with implications in cancer and beyond.

AXL Inhibition Represents a Novel Therapeutic Approach in BCR-ABL Negative Myeloproliferative Neoplasms.

BCR-ABL negative myeloproliferative neoplasms (MPNs) consist of essential thrombocythemia, polycythemia vera, and myelofibrosis. The majority of patients harbor the JAK2-activating mutation V617F. JAK2 inhibitors were shown to reduce symptom burden and splenomegaly in MPN patients. However, treatment options are limited after failure of JAK2 inhibitors. AXL, a member of the TAM family of receptor tyrosine kinases, mediates survival and therapy resistance of different myeloid cancers including acute myeloid leukemia and chronic myeloid leukemia. We studied the relevance of AXL as a target in MPN using primary patient cells and preclinical disease models. We found that AXL is abundantly activated in MPN cells and that its ligand growth arrest-specific gene 6 is upregulated in MPN patients. Pharmacologic and genetic blockade of AXL impaired viability, decreased proliferation and increased apoptosis of MPN cells. Interestingly, ruxolitinib treatment induced increased phosphorylation of AXL indicating that activation of AXL might mediate resistance to ruxolitinib. Consistently, the AXL inhibitor bemcentinib exerted additive effects with ruxolitinib via impaired STAT3, STAT5, and AKT signaling. Both agents had activity when employed alone and exerted an additive effect on survival and splenomegaly in vivo. Moreover, bemcentinib treatment normalized red blood cell count and hemoglobin levels in vivo. Thus, our data indicate that AXL inhibition represents a novel treatment option in MPN warranting clinical investigation.

Influence of Androgens on Immunity to Self and Foreign: Effects on Immunity and Cancer.

It is well-known that sex hormones can directly and indirectly influence immune cell function. Different studies support a suppressive role of androgens on different components of the immune system by decreasing antibody production, T cell proliferation, NK cytotoxicity, and stimulating the production of anti-inflammatory cytokines. Androgen receptors have also been detected in many different cells of hematopoietic origin leading to direct effects of their ligands on the development and function of the immune system. The immunosuppressive properties of androgens could contribute to gender dimorphisms in autoimmune and infectious disease and thereby also hamper immune surveillance of tumors. Consistently, females generally are more prone to autoimmunity, while relatively less susceptible to infections, and have lower incidence and mortality of the majority of cancers compared to males. Some studies show that androgen deprivation therapy (ADT) can induce expansion of naïve T cells and increase T-cell responses. Emerging clinical data also reveal that ADT might enhance the efficacy of various immunotherapies including immune checkpoint blockade. In this review, we will discuss the potential role of androgens and their receptors in the immune responses in the context of different diseases. A particular focus will be on cancer, highlighting the effect of androgens on immune surveillance, tumor biology and on the efficacy of anti-cancer therapies including emerging immune therapies.

Sexual dimorphism in solid and hematological malignancies.

Cancer represents a leading cause of death with continuously increasing incidence worldwide. Many solid cancer types in non-reproductive organs are significantly more frequent and deadly in males compared to females. This sex-biased difference is also present in hematologic malignancies. In this review, we present an overview about sex differences in cancer with a focus on leukemia. We discuss mechanisms potentially underlying the observed sex-biased imbalance in cancer incidence and outcome including sex hormones, sex chromosomes, and immune responses. Besides affecting the pathobiology of cancers, sex differences can also influence drug responses, most notably those to immune checkpoint blockers. Therefore, sex should become a relevant factor in clinical trial design in order to avoid over- or under-treatment of one sex.