Natural Killer Cell Immune Surveillance of Cancer

Microenvironments that tumor cells encounter are different between primary tumor, during metastasis, and at the site of metastasis, suggesting potential differences in immune surveillance of primary tumor and metastasis. Metastatic spread is the main contributing factor that results in 90% of solid tumor deaths. Studying and identifying targetable entities in the metastatic cascade would be exceptionally beneficial for patient treatment. These mechanisms may be cancer cell intrinsic or mediated by other cells of the body. Epithelial-mesenchymal transition (EMT) is a key reversible process in which cancer cells transition into highly motile and invasive cells for dissemination. EMT is considered a critical and initiating step in metastasis. After EMT, only a tiny proportion of cells successfully metastasize; supporting the notion of metastasis-specific immune surveillance. EMT involves extensive molecular reprogramming of cells conferring many clinically-relevant features to cancer cells and affect tumor cell interactions within and outside the tumor microenvironment. Here, we will outline general principles of EMT and published works on the interactions with the immune system. This review will highlight the potential immunological consequences of EMT and the impact on tumor immune surveillance. Natural Killer (NK) cells are known to be the first line of defense against malignant cells and are critical for surveilling and eradicating tumors. Utilizing this knowledge of NK cells with in vitro and in vivo models of EMT, we investigated the role of NK cells in the context of metastasis-specific immune surveillance. Probing the molecular changes during EMT and known NK ligands revealed a skewing toward activation of NK cells upon EMT. We identified two adhesion molecules on some tumor cell lines that drive the balance of NK activation in vitro, E-cadherin and Cell Adhesion Molecule 1 (CADM1). Deletion of the activating CADM1 ligand revealed an escape from NK-mediated immune surveillance. This loss correlates to two lung and one breast cancer patient cohorts showing reduced survival and metastatic spread in CADM1 low populations. We further determined the NK-specific surveillance and possible therapeutic relevance of CADM1 re-expression. Our data demonstrated a metastasis-specific immune surveillance mechanism. Further, this mechanism was mediated by NK cells. Finally, we defined a novel function of a bone fide tumor suppressor, CADM1, in tumor immune escape. Taken together our data reveals a novel role for CADM1 and two avenues for therapeutic exploitation: EMT and boosting NK functions.PHDImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/147516/1/ramshorn_1.pd

Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation

Purpose: The graft-versus-tumor (GVT) effect is a potent form of immunotherapy against many hematologic malignancies and some solid tumors. The beneficial GVT effect after allogeneic bone marrow transplantation (BMT) is tightly linked to its most significant complication, graft-versus-host disease (GVHD). The role of interleukin-6 (IL-6) after allogeneic BMT is not well understood. This study used a series of complementary knockout and antibody blockade strategies to analyze the impact of IL-6 in multiple clinically relevant murine models of GVHD and GVT

Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality

While miRNAs are increasingly linked to various immune responses, whether they can be targeted for regulating in vivo inflammatory processes such as endotoxin-induced Gram-negative sepsis is not known. Production of cytokines by the dendritic cells (DCs) plays a critical role in response to endotoxin, lipopolysaccharide (LPS). We profiled the miRNA and mRNA of CD11c+ DCs in an unbiased manner and found that at baseline, miR-142-3p was among the most highly expressed endogenous miRs while IL-6 was among the most highly expressed mRNA after LPS stimulation. Multiple computational algorithms predicted the IL-6 3′ untranslated region (UTR) to be a target of miR-142-3p. Studies using luciferase reporters carrying wild-type (WT) and mutant IL-6 3′UTR confirmed IL-6 as a target for miR-142-3p. In vitro knockdown and overexpression studies demonstrated a critical and specific role for miR142-3p in regulating IL-6 production by the DCs after LPS stimulation. Importantly, treatment of only WT but not the IL-6–deficient (IL-6−/−) mice with locked nucleic acid (LNA)–modified phosphorothioate oligonucleotide complementary to miR 142-3p reduced endotoxin-induced mortality. These results demonstrate a critical role for miR-142-3p in regulating DC responses to LPS and provide proof of concept for targeting miRs as a novel strategy for treatment of endotoxin-induced mortality