Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.2 of 26 role in pathogenesis [3]. Yet, despite the seemingly linear order of events, the impact of mutations, selective dimerization, negative pathway regulation, and post-translational modifications of pathway members has branded the JAK-STAT axis a complex signaling cascade, of which many regulatory processes are still poorly understood.STATs have emerged as somewhat of a double-edged sword, being widely explored in the context of cancer. While several members of the STAT family, which encompasses STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 as a whole, have been linked to tumor initiation and progression (STAT3 and STAT5), others are integral in antitumor defense and the maintenance of an effective and long-term immune response (STAT1 and STAT2) through evolutionarily conserved programs [1]. With increasing emphasis on immune-based agents as important therapeutics in the fight against solid tumor growth and spread, understanding the function of STAT specificity, redundancy, and connectedness in cancer is a critical component of achieving immunotherapeutic augmentation and success.Here, we investigate the good and the bad of STAT signaling in the context of immune regulation and cancer, and discuss how STATs can be targeted to bolster antitumor immune defense. JAK-STAT Signaling and InterferonsThe presence of stimulatory or inhibitory signals governs the innate and adaptive immune activity that controls both effective immune surveillance and facilitates escape. Such signals determine the fate of plastic immune cells, such as T lymphocytes, and regulate their recruitment, survival, status, and eventual death ...

The era of targeted therapies has seen significant improvements in depth of response, progression-free survival, and overall survival for patients with multiple myeloma. Despite these improvements in clinical outcome, patients inevitably relapse and require further treatment. Drug-resistant dormant myeloma cells that reside in specific niches within the skeleton are considered a basis of disease relapse but remain elusive and difficult to study. Here, we developed a method to sequence the transcriptome of individual dormant myeloma cells from the bones of tumor-bearing mice. Our analyses show that dormant myeloma cells express a distinct transcriptome signature enriched for immune genes and, unexpectedly, genes associated with myeloid cell differentiation. These genes were switched on by coculture with osteoblastic cells. Targeting AXL, a gene highly expressed by dormant cells, using small-molecule inhibitors released cells from dormancy and promoted their proliferation. Analysis of the expression of AXL and coregulated genes in human cohorts showed that healthy human controls and patients with monoclonal gammopathy of uncertain significance expressed higher levels of the dormancy signature genes than patients with multiple myeloma. Furthermore, in patients with multiple myeloma, the expression of this myeloid transcriptome signature translated into a twofold increase in overall survival, indicating that this dormancy signature may be a marker of disease progression. Thus, engagement of myeloma cells with the osteoblastic niche induces expression of a suite of myeloid genes that predicts disease progression and that comprises potential drug targets to eradicate dormant myeloma cells.

The lack of targeted therapies available for triple-negative breast cancer (TNBC) patients who fail to respond to first-line chemotherapy has sparked interest in immunotherapeutic approaches. However, trials utilizing checkpoint inhibitors targeting the PD-1/PD-L1 axis in TNBC have had underwhelming responses. Here, we investigated the interplay between type I IFN signaling and the PD-1/PD-L1 axis and tested the impact of combining IFN inducers, as immune activators, with anti-PD-1, to induce an antimetastatic immune response. Using models of TNBC, we demonstrated an interplay between type I IFN signaling and tumor cell PD-L1 expression that affected therapeutic response. The data revealed that the type I IFN-inducer poly(I:C) was an effective immune activator and antimetastatic agent, functioning better than anti-PD-1, which was ineffective as a single agent. Poly(I:C) treatment induced PD-L1 expression on TNBC cells, and combined poly(I:C) and anti-PD-1 treatment prolonged metastasis-free survival in a neoadjuvant setting via the induction of a tumor-specific T-cell response. Use of this combination in a late treatment setting did not impact metastasis-free survival, indicating that timing was critical for immunotherapeutic benefit. Together, these data demonstrated anti-PD-1 as an ineffective single agent in preclinical models of TNBC. However, type I IFN inducers were effective immune activators, and neoadjuvant trials combining them with anti-PD-1 to induce a sustained antitumor immune response are warranted. .

The latency associated with bone metastasis emergence in castrate‐resistant prostate cancer is attributed to dormancy, a state in which cancer cells persist prior to overt lesion formation. Using single‐cell transcriptomics and ex vivo profiling, we have uncovered the critical role of tumor‐intrinsic immune signaling in the retention of cancer cell dormancy. We demonstrate that loss of tumor‐intrinsic type I IFN occurs in proliferating prostate cancer cells in bone. This loss suppresses tumor immunogenicity and therapeutic response and promotes bone cell activation to drive cancer progression. Restoration of tumor‐intrinsic IFN signaling by HDAC inhibition increased tumor cell visibility, promoted long‐term antitumor immunity, and blocked cancer growth in bone. Key findings were validated in patients, including loss of tumor‐intrinsic IFN signaling and immunogenicity in bone metastases compared to primary tumors. Data herein provide a rationale as to why current immunotherapeutics fail in bone‐metastatic prostate cancer, and provide a new therapeutic strategy to overcome the inefficacy of immune‐based therapies in solid cancers.