Primary Tumors Limit Metastasis Formation through Induction of IL15-Mediated Cross-Talk between Patrolling Monocytes and NK Cells

Abstract

Metastases are responsible for the vast majority of cancerrelated deaths. Although tumor cells can become invasive early during cancer progression, metastases formation typically occurs as a late event. How the immune response to primary tumors may dictate this outcome remains poorly understood, which hampers our capacity to manipulate it therapeutically. Here, we used a twostep experimental model, based on the highly aggressive B16F10 melanoma, that temporally segregates the establishment of primary tumors (subcutaneously) and the formation of lung metastases (from intravenous injection). This allowed us to identify a protective innate immune response induced by primary tumors that inhibits experimental metastasis. We found that in the presence of primary tumors, increased numbers of natural killer (NK) cells with enhanced IFNg, granzyme B, and perforin production were recruited to the lung upon metastasis induction. These changes were mirrored by a local accumulation of patrolling monocytes and macrophages with high expression of MHC class II and NOS2. Critically, the protective effect on metastasis was lost upon patrolling monocyte or NK cell depletion, IL15 neutralization, or IFNg ablation. The combined analysis of these approaches allowed us to establish a hierarchy in which patrolling monocytes, making IL15 in response to primary tumors, activate NK cells and IFNg production that then inhibit lung metastasis formation. This work identifies an innate cell network and the molecular determinants responsible for "metastasis immunosurveillance," providing support for using the key molecular mediator, IL15, to improve immunotherapeutic outcomes.

Interleukin-15-Cultured Dendritic Cells Enhance Anti-Tumor Gamma Delta T Cell Functions through IL-15 Secretion

“…Its non-redundant role is reflected by the fact that CD8 + memory T cells and NK cells are absent in IL-15-deficient environments ( 45 , 46 ), and the lack of IFN-γ-producing γδ T cells in IL-15 −/− mice ( 47 ). Moreover, the anti-tumor effect of IL-15 on the immune system has been well-documented in experimental systems ( 48 – 50 ). Concerning IL-15-mediated γδ T cell activation, our findings are in line with data describing γδ T cell proliferation in rhesus macaques after continuous administration of IL-15 ( 51 ) and an increase in absolute γδ T cell counts, accompanied by an upsurge in proliferating γδ T cells, in the first-in-human trial of recombinant IL-15 in cancer patients ( 52 ).…”

Monocyte heterogeneity and functions in cancer

“…3 Building upon these findings, IL-15 was identified as a critical monocyte-derived signaling molecule required for recruitment of cytotoxic NK cells to metastatic tumor sites. 69 In human non-small cell lung cancer tumors, CD16 + monocytes are lower in the tumor microenvironment compared to adjacent nonmalignant tissue, which is associated with reduced infiltration of CD16 + NK cells. 38 These findings suggest that the relationship between nonclassical monocytes and NK cells first observed in mouse models of experimental metastasis may be relevant to human solid tumors, although this and interactions with other immune cells requires further investigation.…”

“…The long lifespan and patrolling activities of nonclassical monocytes make them particularly well suited to scavenge tumor cells and debris. In the context of cancer, nonclassical monocytes migrate toward metastatic sites within the lung, where they engulf tumor material and generate cytokines that regulate antitumor immunity . Tumor‐derived exosomes also expand bone marrow pools of patrolling monocytes, which appears to initiate an immune surveillance cascade that prevents metastatic seeding …”

“…While nonclassical monocytes continue to uptake tumor material in the absence of NK cells, their protective effect against tumor metastasis is lost . Building upon these findings, IL‐15 was identified as a critical monocyte‐derived signaling molecule required for recruitment of cytotoxic NK cells to metastatic tumor sites . In human non‐small cell lung cancer tumors, CD16 + monocytes are lower in the tumor microenvironment compared to adjacent nonmalignant tissue, which is associated with reduced infiltration of CD16 + NK cells .…”

“…78 In addition to interacting with T cells, multiple reports have demonstrated that nonclassical monocytes are important for recruitment of NK cells to tumors, particularly within metastatic sites. 3,69,70 Ly6C lo monocytes express high levels of NK chemoattractants such as CCL3, CCL4, and CCL5 and are required for NK cell recruitment to metastatic tumors within lung. 3 While nonclassical monocytes continue to uptake tumor material in the absence of NK cells, their protective effect against tumor metastasis is lost.…”