In fact, monocyte/macrophage lineage cells accumulate in numerous malignant entities

In fact, monocyte/macrophage lineage cells accumulate in numerous malignant entities. transcriptomic, and functional skewing towards a M1-like phenotype. Overall, we introduce CD137 as a positive immune checkpoint on human monocytes/macrophages, which can have therapeutic implications especially in view of synergistic effects when combining CD137 agonists with tumor-targeting antibodies. Subject terms: Translational research, Immunotherapy Introduction To date, tumor immunosurveillance and tumor immunoediting are well-established concepts. Moreover, immunotherapy represents one the most appealing anti-cancer methods [1]. Two key strategies are currently intensely pursued: adoptive transfer of genetically designed immune cells (e.g., chimeric antigen receptor/CAR T-cells) or application of brokers that activate the patients immune system (by e.g., blockade of unfavorable immune checkpoints) Allopurinol sodium and thereby re-invigorate intrinsic antitumor immunity. Immune checkpoint receptors are membrane molecules on immune cells, which upon binding to their cognate ligand on tumors or tumor-associated cells can negatively (i.e., inhibitory receptors) or positively (i.e., stimulatory receptors) impact the immune cells function. Examples for inhibitory receptors that are successfully targeted in the clinical practice include programmed cell Zfp264 death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 [2]. The cell surface glycoprotein CD137, which is also known as 4-1BB, belongs to the group of co-stimulatory immune receptors and is a member of the TNF receptor superfamily. It is preferentially found on activated T-cells and regulatory T-cells (TRegs) but also innate immune cells, such as natural killer (NK-) cells, neutrophils, and monocytes can express CD137 [3C5]. Antigen-presenting cells, such as dendritic cells predominantly express, especially in response to Allopurinol sodium stimulatory trigger, its natural ligand CD137-L. The CD137/CD137-L interaction prospects to the recruitment of TNF receptor-associated factors 1/2 and the downstream activation of the nuclear factor kappa B transcriptional pathway [6]. In T-cells, CD137 crosslinking delivers a potent co-stimulatory transmission as it promotes T-cell proliferation and formation of memory cells, enhances survival, and increases the production of interferon- (IFN-) and interleukin-2 (IL-2) [7]. Moreover, CD137 signaling has been shown to hold the potential to reprogram tolerogenic TRegs into effector T-cells with antitumor activity [4]. In fact, incorporating the intracellular signaling domain name of CD137 fosters clinical activity of CAR T-cells further highlighting its importance for antitumor immunity [8]. Similarly, NK cells respond to CD137 stimulation with increased proliferation, production of IFN-, and the ability to perform antibody-dependent cell-mediated cytotoxicity (ADCC) against malignant cells [9]. Consistent with its co-stimulatory function, agonistic monoclonal antibodies (mAbs) against CD137 have elicited effective antitumor immune responses in preclinical Allopurinol sodium models that have been mainly attributed to the activation of T-cells and/or NK cells [10C12]. Actually, CD137-engaging mAbs, such as Urelumab or Utomilumab have already entered clinical trials for different types of tumors (e.g., melanoma or lung malignancy) demonstrating their efficacy [13, 14]. However, the role of CD137 signaling in human monocytes/macrophages remains relatively unexplored. In fact, monocyte/macrophage lineage cells accumulate in numerous malignant entities. Tumor-associated monocytes/macrophages (TAMs) regularly display a pro-tumoral M2 phenotype. They do not only provide nurturing signals by e.g., stimulating angiogenesis but also inhibit antitumor immune responses [15]. At the same Allopurinol sodium time, several reports highlight the potential antitumor function of monocytes/macrophages as mediators of antibody-based therapies against malignancy, such as anti-CD20 or anti-Her2 mAbs or potentiators of adaptive immune responses [16, 17]. Importantly, intrinsic tumoricidal capacity is retained in the M2-like cells and can be reactivated by disrupting M2-promoting signals leading to the formation of a rather immunoreactive M1 phenotype [18]. Given their central role in tumor development and tumor progression as well as their functional plasticity, monocytes/macrophages symbolize ideal candidates for therapeutic interventions. However, to fully unleash their tumoricidal capacity, it can be necessary to previously overcome certain immunosuppressive hurdles. Blocking the unfavorable immune checkpoint CD47.