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CCL3 Enhances Antitumor Immune Priming in the Lymph Node via IFN? with Dependency on Natural Killer Cells.

ABSTRACT: Lymph node (LN) plays a critical role in tumor cell survival outside of the primary tumor sites and dictates overall clinical response in many tumor types (1, 2). Previously, we and others have demonstrated that CCL3 plays an essential role in orchestrating T cell-antigen-presenting cell (APC) encounters in the draining LN following vaccination, and such interactions enhance the magnitude of the memory T cell pool (3-5). In the current study, we investigate the cellular responses in the tumor-draining lymph nodes (TDLNs) of a CCL3-secreting CT26 colon tumor (L3TU) as compared to wild-type tumor (WTTU) during the priming phase of an antitumor response (?10?days). In comparison to WTTU, inoculation of L3TU resulted in suppressed tumor growth, a phenomenon that is accompanied by altered in vivo inflammatory responses on several fronts. Autologous tumor-derived CCL3 (aCCL3) secretion by L3TU bolstered the recruitment of T- and B-lymphocytes, tissue-migratory CD103+ dendritic cells (DCs), and CD49b+ natural killer (NK) cells, resulting in significant increases in the differentiation and activation of multiple Interferon-gamma (IFN?)-producing leukocytes in the TDLN. During this early phase of immune priming, NK cells constitute the major producers of IFN? in the TDLN. CCL3 also enhances CD8+ T cell proliferation and differentiation by augmenting DC capacity to drive T cell activation in the TDLN. Our results revealed that CCL3-dependent IFN? production and CCL3-induced DC maturation drive the priming of effective antitumor immunity in the TDLN.

SUBMITTER: Allen F

PROVIDER: S-EPMC5660298 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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CCL3 Enhances Antitumor Immune Priming in the Lymph Node <i>via</i> IFNγ with Dependency on Natural Killer Cells.

Allen Frederick F Rauhe Peter P Askew David D Tong Alexander A AA Nthale Joseph J Eid Saada S Myers Jay T JT Tong Caryn C Huang Alex Y AY

Frontiers in immunology 20171023

Lymph node (LN) plays a critical role in tumor cell survival outside of the primary tumor sites and dictates overall clinical response in many tumor types (1, 2). Previously, we and others have demonstrated that CCL3 plays an essential role in orchestrating T cell-antigen-presenting cell (APC) encounters in the draining LN following vaccination, and such interactions enhance the magnitude of the memory T cell pool (3-5). In the current study, we investigate the cellular responses in the tumor-dr ...[more]

PMID: 29109732

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Project description:The goal of this project is todetermine if natural killer (NK) cells could be able to control HIV replication and reduce or eliminate viral reservoirs leading to HIV cure or a functional cure. Despite thirty years of work and significant progress, HIV infection continues to be an incurable disease. Antiretroviral therapy (ART) has significantly decreased the morbidity and mortality, but lifelong treatment is merely suppressive and does not cure HIV/AIDS. This is because of the existence of a reservoir of viral DNA+ (vDNA+) in cells of the lymphoid tissues with an intact provirus that is thought capable of initiating new rounds of HIV replication (i.e. latency). In addition to this inducible reservoir data suggest ongoing low-level virus replication and persistence in lymphatic tissues of some patients that is related to suboptimal drug levels in these tissues. Strategies are needed that can address both issues. NK cells are innate immune effectors that recognize virally infected targets through a cadre of activating and inhibitory receptors but become dysfunctional in HIV infected people. Strikingly, African green monkeys (AGM) and sooty mangabeys mount a strong control of viral replication in lymph node follicles shortly after the viremia peak that lasts throughout infection. Several mechanisms have been proposed to be implicated in the strong control of viral replication in natural host’s lymph nodes, such as NK cell-mediated control. Indeed, we have recently shown that NK cells could migrate into the b cells follicles in a CXCR5 dependent manner and thus participate to the elimination of viral replication. Thus the purpose of this study is too compare at the transcriptomic level different subset of NK cell isolated from blood and peripheral lymph node of chronically infected AGM to identify a transcriptomic signature which could be linked to an efficient control of SIV replication. This results could then provide a new aproche which could be exploited to generate functional NK cells against HIV in infected patients.

Project description:Natural killer group 2D (NKG2D) is an activating receptor of natural killer (NK) cells and other lymphocytes that mediates lysis of malignant cells through recognition of stress-induced ligands such as MICA and MICB. Such ligands are broadly expressed by cancer cells of various origins and serve as targets for adoptive immunotherapy with effector cells endogenously expressing NKG2D or carrying an NKG2D-based chimeric antigen receptor (CAR). However, shedding or downregulation of NKG2D ligands (NKG2DL) can prevent NKG2D activation, resulting in escape of cancer cells from NKG2D-dependent immune surveillance. To enable tumor-specific targeting of NKG2D-expressing effector cells independent of membrane-anchored NKG2DLs, we generated a homodimeric recombinant antibody which harbors an N-terminal single-chain fragment variable (scFv) antibody domain for binding to NKG2D, linked via a human IgG4 Fc region to a second C-terminal scFv antibody domain for recognition of the tumor-associated antigen ErbB2 (HER2). The ability of this molecule, termed NKAB-ErbB2, to redirect NKG2D-expressing effector cells to ErbB2-positive tumor cells of different origins was investigated using peripheral blood mononuclear cells, ex vivo expanded NK cells, and NK and T cells engineered with an NKG2D-based chimeric receptor. On its own, bispecific NKAB-ErbB2 increased lysis of ErbB2-positive breast carcinoma cells by peripheral blood-derived NK cells endogenously expressing NKG2D more effectively than an ErbB2-specific IgG1 mini-antibody able to induce antibody-dependent cell-mediated cytotoxicity via activation of CD16. Furthermore, NKAB-ErbB2 synergized with NK-92 cells or primary T cells engineered to express an NKG2D-CD3ζ chimeric antigen receptor (NKAR), leading to targeted cell killing and greatly enhanced antitumor activity, which remained unaffected by soluble MICA known as an inhibitor of NKG2D-mediated natural cytotoxicity. In an immunocompetent mouse glioblastoma model mimicking low or absent NKG2DL expression, the combination of NKAR-NK-92 cells and NKAB-ErbB2 effectively suppressed outgrowth of ErbB2-positive tumors, resulting in treatment-induced endogenous antitumor immunity and cures in the majority of animals. Our results demonstrate that combining an NKAB antibody with effector cells expressing an activating NKAR receptor represents a powerful and versatile approach to simultaneously enhance tumor antigen-specific as well as NKG2D-CAR and natural NKG2D-mediated cytotoxicity, which may be particularly useful to target tumors with heterogeneous target antigen expression.

Dataset Information

CCL3 Enhances Antitumor Immune Priming in the Lymph Node via IFN? with Dependency on Natural Killer Cells.

Publications

CCL3 Enhances Antitumor Immune Priming in the Lymph Node <i>via</i> IFNγ with Dependency on Natural Killer Cells.

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