A Bacterial and Ganglioside-based Nanoparticle Initiates Reprogramming of Macrophages and Promotes Antitumor Phenotypes.

Macrophages represent the most abundant immune component of the tumor microenvironment and often exhibit protumorigenic (M2-like) phenotypes that contribute to disease progression. Despite their generally accepted protumorigenic role, macrophages can also display tumoricidal (or M1-like) behavior, revealing that macrophages can be functionally reprogrammed, depending on the cues received within the tumor microenvironment. Moreover, such plasticity may be achieved by pharmacologic or biologic interventions.

Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity.

Although the signaling events that induce different forms of programmed cell death are well defined, the subsequent immune responses to dying cells in the context of cancer remain relatively unexplored. Necroptosis occurs downstream of the receptor-interacting protein kinases RIPK1 and RIPK3, whose activation leads to lytic cell death accompanied by de novo production of proinflammatory mediators. Here, we show that ectopic introduction of necroptotic cells to the tumor microenvironment promotes BATF3 cDC1- and CD8 leukocyte-dependent antitumor immunity accompanied by increased tumor antigen loading by tumor-associated antigen-presenting cells.

β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8 T Cells and Undermines Checkpoint Inhibitor Therapy.

The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8 T-cell frequency and functional orientation within the tumor microenvironment is regulated by β-adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies-physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β-AR knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models.

HSPs drive dichotomous T-cell immune responses via DNA methylome remodelling in antigen presenting cells.

Immune responses primed by endogenous heat shock proteins, specifically gp96, can be varied, and mechanisms controlling these responses have not been defined. Immunization with low doses of gp96 primes T helper type 1 (Th1) immune responses, whereas high-dose immunization primes responses characterized by regulatory T (Treg) cells and immunosuppression. Here we show gp96 preferentially engages conventional and plasmacytoid dendritic cells (pDCs) under low and high doses, respectively, through CD91.

The Granulocyte Progenitor Stage Is a Key Target of IRF8-Mediated Regulation of Myeloid-Derived Suppressor Cell Production.

Alterations in myelopoiesis are common across various tumor types, resulting in immature populations termed myeloid-derived suppressor cells (MDSCs). MDSC burden correlates with poorer clinical outcomes, credited to their ability to suppress antitumor immunity. MDSCs consist of two major subsets, monocytic and polymorphonuclear (PMN).

Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes.

Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive network that drives cancer escape by disabling T cell adaptive immunity. The prevailing view is that MDSC-mediated immunosuppression is restricted to tissues where MDSC co-mingle with T cells. Here we show that splenic or, unexpectedly, blood-borne MDSC execute far-reaching immune suppression by reducing expression of the L-selectin lymph node (LN) homing receptor on naïve T and B cells.

Relevance of Interferon Regulatory Factor-8 Expression in Myeloid-Tumor Interactions.

Perturbations in myelopoiesis are a common feature in solid tumor biology, reflecting the central premise that cancer is not only a localized affliction but also a systemic disease. Because the myeloid compartment is essential for the induction of adaptive immunity, these alterations in myeloid development contribute to the failure of the host to effectively manage tumor progression. These "dysfunctional" myeloid cells have been coined myeloid-derived suppressor cells (MDSCs).

Tumor-induced myeloid dysfunction and its implications for cancer immunotherapy.

Immune function relies on an appropriate balance of the lymphoid and myeloid responses. In the case of neoplasia, this balance is readily perturbed by the dramatic expansion of immature or dysfunctional myeloid cells accompanied by a reciprocal decline in the quantity/quality of the lymphoid response. In this review, we seek to: (1) define the nature of the atypical myelopoiesis observed in cancer patients and the impact of this perturbation on clinical outcomes; (2) examine the potential mechanisms underlying these clinical manifestations; and (3) explore potential strategies to restore normal myeloid cell differentiation to improve activation of the host antitumor immune response.

Mild cold-stress depresses immune responses: Implications for cancer models involving laboratory mice.

Physiologically accurate mouse models of cancer are critical in the pre-clinical development of novel cancer therapies. However, current standardized animal-housing temperatures elicit chronic cold-associated stress in mice, which is further increased in the presence of tumor. This cold-stress significantly impacts experimental outcomes.

Establishment of tumor-associated immunity requires interaction of heat shock proteins with CD91.

Host antitumor adaptive immune responses are generated as a result of the body's immunosurveillance mechanisms. How the antitumor immune response is initially primed remains unclear, given that soluble tumor antigens generally are quantitatively insufficient for cross-priming and tumors generally lack the classical pathogen-associated molecular patterns to activate costimulation and initiate cross-priming. We explored the interaction of the tumor-derived heat shock proteins (HSP) with their common receptor (CD91) on antigen-presenting cells (APC) as a mechanism for host-priming of T-cell-mediated antitumor immunity.

Identification of the cellular sentinels for native immunogenic heat shock proteins in vivo.

Select members of the heat shock proteins (HSPs) family, such as gp96, elicit immune responses specific to their chaperoned peptides. Although immunologic effects of HSPs on APCs described to date have largely been demonstrated with cell lines or primary cells in culture, their collective responses in vitro have been consistent with priming immune responses. In this study, we examine the physiologically relevant APCs in mice that are targeted after vaccination with native, murine HSPs, and we characterize those cells.

CD91-Dependent Modulation of Immune Responses by Heat Shock Proteins: A Role in Autoimmunity.

Heat shock proteins (HSPs) have been known for decades for their ability to protect cells under stressful conditions. In the 1980s a new role was ascribed for several HSPs given their ability to elicit specific immune responses in the setting of cancer and infectious disease. These immune responses have primarily been harnessed for the immunotherapy of cancer in the clinical setting.

Human dendritic cells adenovirally-engineered to express three defined tumor antigens promote broad adaptive and innate immunity.

Dendritic cell (DC) immunotherapy has shown a promising ability to promote anti-tumor immunity in vitro and in vivo. Many trials have tested single epitopes and single antigens to activate single T cell specificities, and often CD8(+) T cells only. We previously found that determinant spreading and breadth of antitumor immunity correlates with improved clinical response.

A role for the heat shock protein-CD91 axis in the initiation of immune responses to tumors.

For over 100 years, it has been established that tumor-specific immune responses can frequently be detected in the tumor-bearing host. Whether or not these immune responses are capable of controlling the growth of the tumor is influenced by many factors. However, the mechanism by which the immune responses are initiated in the first place has remained a dilemma.

Francisella tularensis LVS-induced Interleukin-12 p40 cytokine production mediates dendritic cell migration through IL-12 Receptor β1.

Three cytokines use the IL-12p40 cytokine subunit namely: IL-12p70 (IL-12-comprised of IL-12p40 and IL-12p35), IL-23 (comprised of the IL-12p40 and IL-23p19 subunits) and homodimeric IL-12p40 (IL-12(p40)(2)). Following activation, immature dendritic cells (DCs) upregulate the chemokine receptor Chemokine-C-Receptor 7 (CCR7), and migrate in response to homeostatic chemokines such as chemokine (C-C motif) ligand 19 (CCL19). Induction of the cytokine IL-12p40 in response to pathogen-exposure, likely in its homodimeric form, is one of the primary events that mediates migration of DCs in response to CCL19.

Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis.

The importance of T helper type 1 (Th1) cell immunity in host resistance to the intracellular bacterium Francisella tularensis is well established. However, the relative roles of interleukin (IL)-12-Th1 and IL-23-Th17 cell responses in immunity to F. tularensis have not been studied.