Abstract:We present a new foundational role for CXCR3+ monocytes/macrophages in the process of tumor engraftment in the lung. CXCR3 is associated with monocytic and lymphocytic infiltration of inflamed or tumor-bearing lung. Although the requirement for tumor-expressed CXCR3 in metastatic engraftment has been demonstrated, the role of monocyte-expressed CXCR3 had not been appreciated. In a murine model of metastatic-like melanoma, engraftment was coordinate with CXCR3+ monocyte/macrophage accumulation in the lungs and … Show more
“…Patrolling monocytes have been shown to reduce metastasis by scavenging tumor material and promoting natural killer cell recruitment and activation [1]. Inflammatory monocytes have been shown to potentially facilitate cancer cell extravasation and their engraftment by replenishing the pool of macrophages present at the secondary site of tumor formation [20], [21]. However, these studies did not study direct engagement between inflammatory monocytes and tumor cells but rather the effects of monocytes after they had been recruited to the metastatic site.…”
Metastasis is the leading cause of cancer-related deaths. Recent developments in cancer immunotherapy have shown exciting therapeutic promise for metastatic patients. While most therapies target T cells, other immune cells, such as monocytes, hold great promise for therapeutic intervention. In our study, we provide primary evidence of direct engagement between human monocytes and tumor cells in a 3D vascularized microfluidic model. We first characterize the novel application of our model to investigate and visualize at high resolution the evolution of monocytes as they migrate from the intravascular to the extravascular micro-environment. We also demonstrate their differentiation into macrophages in our all-human model. Our model replicates physiological differences between different monocyte subsets. In particular, we report that inflammatory, but not patrolling, monocytes rely on actomyosin based motility. Finally, we exploit this platform to study the effect of monocytes, at different stages of their life cycle, on cancer cell extravasation. Our data demonstrates that monocytes can directly reduce cancer cell extravasation in a non-contact dependent manner. In contrast, we see little effect of monocytes on cancer cell extravasation once monocytes transmigrate through the vasculature and are macrophage-like. Taken together, our study brings novel insight into the role of monocytes in cancer cell extravasation, which is an important step in the metastatic cascade. These findings establish our microfluidic platform as a powerful tool to investigate the characteristics and function of monocytes and monocyte-derived macrophages in normal and diseased states. We propose that monocyte-cancer cell interactions could be targeted to potentiate the anti-metastatic effect we observe in vitro, possibly expanding the milieu of immunotherapies available to tame metastasis.
“…Patrolling monocytes have been shown to reduce metastasis by scavenging tumor material and promoting natural killer cell recruitment and activation [1]. Inflammatory monocytes have been shown to potentially facilitate cancer cell extravasation and their engraftment by replenishing the pool of macrophages present at the secondary site of tumor formation [20], [21]. However, these studies did not study direct engagement between inflammatory monocytes and tumor cells but rather the effects of monocytes after they had been recruited to the metastatic site.…”
Metastasis is the leading cause of cancer-related deaths. Recent developments in cancer immunotherapy have shown exciting therapeutic promise for metastatic patients. While most therapies target T cells, other immune cells, such as monocytes, hold great promise for therapeutic intervention. In our study, we provide primary evidence of direct engagement between human monocytes and tumor cells in a 3D vascularized microfluidic model. We first characterize the novel application of our model to investigate and visualize at high resolution the evolution of monocytes as they migrate from the intravascular to the extravascular micro-environment. We also demonstrate their differentiation into macrophages in our all-human model. Our model replicates physiological differences between different monocyte subsets. In particular, we report that inflammatory, but not patrolling, monocytes rely on actomyosin based motility. Finally, we exploit this platform to study the effect of monocytes, at different stages of their life cycle, on cancer cell extravasation. Our data demonstrates that monocytes can directly reduce cancer cell extravasation in a non-contact dependent manner. In contrast, we see little effect of monocytes on cancer cell extravasation once monocytes transmigrate through the vasculature and are macrophage-like. Taken together, our study brings novel insight into the role of monocytes in cancer cell extravasation, which is an important step in the metastatic cascade. These findings establish our microfluidic platform as a powerful tool to investigate the characteristics and function of monocytes and monocyte-derived macrophages in normal and diseased states. We propose that monocyte-cancer cell interactions could be targeted to potentiate the anti-metastatic effect we observe in vitro, possibly expanding the milieu of immunotherapies available to tame metastasis.
“…1 F ) or day +5 ( Fig. 1G ) post-tumor inoculation (by which time the tumor has engrafted 18,19 ), suggesting that QBKPN treatment can induce anti-tumor immune activity in the context of a growing tumor. Figure 1.…”
Section: Resultsmentioning
confidence: 97%
“… 17 Differences in tumor development were not a consequence of differential engraftment, as prophylactic QBKPN administration did not impact melanoma engraftment into the lungs, assessed two hours post-injection by qualitative RT-PCR for melanoma specific gene products (data not shown). 18 To determine whether QBKPN could be used as a treatment strategy post tumor inoculation, therapeutic administration of QBKPN was tested in tumor-challenged mice. QBKPN treatment decreased tumor burden of B16F10 melanoma when treatment was initiated at day +1 ( Fig.…”
Acute infection is known to induce strong anti-tumor immune responses, but clinical translation has been hindered by the lack of an effective strategy to safely and consistently provoke a therapeutic response. These limitations are overcome with a novel treatment approach involving repeated subcutaneous delivery of a Klebsiella-derived investigational immunotherapeutic, QBKPN. In preclinical models of lung cancer, QBKPN administration consistently showed anti-cancer efficacy, which was dependent on Klebsiella pre-exposure, but was independent of adaptive immunity. Rather, QBKPN induced anti-tumor innate immunity that required NK cells and NKG2D engagement. QBKPN increased NK cells and macrophages in the lungs, altered macrophage polarization, and augmented the production of cytotoxic molecules. An exploratory trial in patients with non-small cell lung cancer demonstrated QBKPN was well tolerated, safe, and induced peripheral immune changes suggestive of macrophage polarization and reduction of PD-1 and PD-L1 expression on leukocytes. These data demonstrate preclinical efficacy, and clinical safety and tolerability, for this cancer immunotherapy strategy that exploits innate anti-tumor immune mechanisms.
“…Additional candidates for tumor recruitment of M-LECP are CXCL12 (SDF-1), a chemokine shown to recruit LYVE-1 + macrophages to adipose tissue via activation of its receptor CXCR4 [23], and CXCR3, a receptor for chemotactic factors CXCL9, CXCL10, and CXCL11 [91]. The potential for the latter receptor to control M-LECP migration is suggested by similar effects on various immune cells including monocytes [15] and mesenchymal stem cells [42]. Both CXCR3 and CXCR4 have been shown to promote lymphangiogenesis [59,120] and metastasis [59,122], which is consistent with their potential role in the recruitment of M-LECP.…”
Section: M-lecp Recruitment To Tumors and Their Intratumoral Traffickingmentioning
confidence: 99%
“…Monocytes, macrophages, stem cells 100% CXCR3 is a chemotactic receptor for stem cells [42], monocytes [15], and other immune cells [67] STAB1 b…”
Tumor lymphatics play a key role in cancer progression as they are solely responsible for transporting malignant cells to regional lymph nodes (LNs), a process that precedes and promotes systemic lethal spread. It is broadly accepted that tumor lymphatic sprouting is induced mainly by soluble factors derived from tumor-associated macrophages (TAMs) and malignant cells. However, emerging evidence strongly suggests that a subset of TAMs, myeloid-lymphatic endothelial cell progenitors (M-LECP), also contribute to the expansion of lymphatics through both secretion of paracrine factors and a self-autonomous mode. M-LECP are derived from bone marrow (BM) precursors of the monocyte-macrophage lineage and characterized by unique coexpression of markers identifying lymphatic endothelial cells (LEC), stem cells, M2-type macrophages, and myeloid-derived immunosuppressive cells. This review describes current evidence for the origin of M-LECP in the bone marrow, their recruitment tumors and intratumoral trafficking, similarities to other TAM subsets, and mechanisms promoting tumor lymphatics. We also describe M-LECP integration into preexisting lymphatic vessels and discuss potential mechanisms and significance of this event. We conclude that improved mechanistic understanding of M-LECP functions within the tumor environment may lead to new therapeutic approaches to suppress tumor lymphangiogenesis and metastasis to lymph nodes.
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