Myeloid reprogramming by JAK inhibition enhances checkpoint blockade therapy

Abstract

Unleashing anti-tumor T cell activity by checkpoint inhibition is effective in many cancer patients but clinical response rates remain limited. Myeloid derived suppressor cells erode antitumor lymphocyte numbers and function, and correlate with resistance to checkpoint inhibitors. By screening small molecule libraries, we identified JAK inhibitors' ability to rescue T cell function. Despite its documented immune suppressive properties, the prototypical JAK inhibitor ruxolitinib enhanced the efficacy of immune checkpoint blockade in cancer. This effect correlated with loss of suppressive gene expression, and acquisition of immunostimulatory molecular markers and T cell stimulatory activity in myeloid cells. In preclinical models, ruxolitinib significantly improved the function and increased the total numbers of activated tumor-infiltrating NK and CD4 T cells compared to checkpoint blockade alone and the efficacy was conditional on granulocytic cells. In addition to myeloid reprogramming in the tumor, ruxolitinib blunts G-CSF signaling in the bone marrow to prevent expression of suppressive and chemotaxis genes in neutrophils. In a clinical trial of Hodgkin lymphoma patients resistant to checkpoint inhibitors, treatment with ruxolitinib significantly reduced neutrophil-to-lymphocyte ratios and levels of suppressive markers in myeloid cells but increased numbers of cytokine-producing T cells. These results support the therapeutic potential of JAK inhibition in combination with checkpoint inhibitors in cancer and highlight the potential of reshaped myeloid immunity to improve immunotherapy.

Janus kinase inhibitor overcomes resistance to immune checkpoint inhibitor treatment in peritoneal dissemination of gastric cancer in C57BL/6 J mice

“…The addition of JAKi induced a more modest and limited increase in cytokine signaling [31]. Simultaneously, it rescued the phenotype of exhausted CD8 + T cells, as observed in mouse models of colon cancer, T cell lymphoma, lung cancer, and pancreatic cancer [31,35,39,40]. Collectively, our findings highlight the potential of JAK as valuable components in combination with ICI therapies to overcome ICI resistance, offering new strategies to enhance anti-tumor responses without compromising crucial immune functions, and emphasizing the importance of understanding the complex interplay between immune signaling pathways in cancer treatment.…”

“…In Zak J. et al's study on JAK1-/-and JAK2-/-MC38 tumor-bearing B6 mice, monocytes showed significantly higher levels of MHC-II transcript and protein in tumors treated with dual ICI + JAKi compared to those treated with dual ICI alone. These results suggested that while JAK1/2 deficiency altered the tumor-immune properties of syngeneic tumors, Ruxolitinib's immunomodulatory effect was at least partially independent of tumor cell-intrinsic JAK signaling [35]. While inhibiting the excessive activation of the JAK-STAT pathway, whether directly hindering tumor proliferation or modulating tumor immunity, can offer therapeutic benefits, the broader utilization of JAK inhibitors in cancer treatment has faced challenges due to their immunosuppressive characteristics [36].…”

Discovery of the Potent and Selective Inhaled Janus Kinase 1 Inhibitor AZD4604 and Its Preclinical Characterization

“…Yet, persistent interferon signaling increases PD-1 expression on T cells via an IFN-responsive element, attenuating T cell antitumor response . Indeed, two recent studies showed that patients with persistent interferon-I (IFN-I) signaling who were refractory to PD-1 checkpoint blockade treatment exhibited progressive CD8 T cell terminal differentiation and progressive disease. , Furthermore, these studies show that JAK inhibition therapy may improve the efficacy of anti-PD-1 therapy by altering T cell differentiation dynamics in patients with persistent IFN-I signaling, thus providing a new strategy to overcome response. Further research into the effect of selective JAK1 inhibitors, such as 16 , in the treatment of chronic Th2 asthma while avoiding opportunistic viral infections would be of interest.…”