An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and ...how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain-containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.
Despite recent advances, many cancers remain refractory to available immunotherapeutic strategies. Emerging evidence indicates that the tolerization of local dendritic cells (DCs) within the tumor ...microenvironment promotes immune evasion. Here, we have described a mechanism by which melanomas establish a site of immune privilege via a paracrine Wnt5a-β-catenin-peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling pathway that drives fatty acid oxidation (FAO) in DCs by upregulating the expression of the carnitine palmitoyltransferase-1A (CPT1A) fatty acid transporter. This FAO shift increased the protoporphyrin IX prosthetic group of indoleamine 2,3-dioxgenase-1 (IDO) while suppressing interleukin(IL)-6 and IL-12 cytokine expression, culminating in enhanced IDO activity and the generation of regulatory T cells. We demonstrated that blockade of this pathway augmented anti-melanoma immunity, enhanced the activity of anti-PD-1 antibody immunotherapy, and suppressed disease progression in a transgenic melanoma model. This work implicates a role for tumor-mediated metabolic reprogramming of local DCs in immune evasion and immunotherapy resistance.
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•Melanomas metabolically reprogram local DCs to induce immune tolerance•Melanoma-derived Wnt5a triggers DC FAO via a β-catenin-PPAR-γ pathway•DC FAO drives IDO enzymatic activity by promoting protoporphyrin IX synthesis•Inhibiting the Wnt5a-β-catenin-CPT1A pathway enhances anti-PD-1 antibody activity
Previous studies suggest that DC tolerization plays a role in tumor-mediated immune evasion. The mechanism by which cancers promote this process remains poorly understood. Zhao et al. demonstrate that melanomas generate a site of immune privilege by driving DC fatty acid oxidation via a Wnt5a-β-catenin-PPAR-γ signaling pathway that culminates in the induction of IDO enzyme activity. Inhibiting this pathway reverses DC tolerization and enhances anti-PD-1 antibody efficacy in a transgenic model of melanoma.
The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further ...studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane-bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti-CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node-derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt-β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy.
Although prolonged genetic pressure has been conjectured to be necessary for the eventual development of tumor immune evasion mechanisms, recent work is demonstrating that early genetic mutations are ...capable of moonlighting as both intrinsic and extrinsic modulators of the tumor immune microenvironment. The indoleamine 2,3-dioxygenase-1 (IDO) immunoregulatory enzyme is emerging as a key player in tumor-mediated immune tolerance. While loss of the tumor suppressor, BIN-1, and the over-expression of cyclooxygenase-2 have been implicated in intrinsic regulation of IDO, recent findings have demonstrated the loss of TβRIII and the upregulation of Wnt5a by developing cancers to play a role in the extrinsic control of IDO activity by local dendritic cell populations residing within tumor and tumor-draining lymph node tissues. Together, these genetic changes are capable of modulating paracrine signaling pathways in the early stages of carcinogenesis to establish a site of immune privilege by promoting the differentiation and activation of local regulatory T cells. Additional investigation of these immune evasion pathways promises to provide opportunities for the development of novel strategies to synergistically enhance the efficacy of the evolving class of T cell-targeted "checkpoint" inhibitors.
In this paper, ozone (O3), water vapor (H2O), carbon monoxide (CO), and peroxide concentrations and photolysis rates measured in the troposphere over the North Atlantic during two Atmospheric ...Chemistry Studies in the Oceanic Environment (ACSOE) aircraft field campaigns are used to calculate the concentration of nitric oxide (NO) required for net photochemical O3 production (nPO3) to be positive (NOcomp). NOcomp tended to show a decrease with altitude, although it was sometimes found to be low in the marine boundary layer (MBL) where H2O concentrations were high and O3 concentrations were low. nPO3 was calculated for the spring when NO data were available and was found to be mostly negative and generally increased from about −0.5 to −0.2 ppbv hr−1 in the MBL to +0.04 ppbv hr−1 at about 7–8 km altitude. The results suggest that much of the lower and middle troposphere over the eastern North Atlantic during spring is in a state of slow net photochemical O3 destruction. However, in the upper troposphere, the system changes to one of net photochemical production, which results from the drier environment and higher NO concentrations. Furthermore, examples of net O3 production were also observed in the lower and middle troposphere associated with either in situ sources of NO or long‐range transport of pollution. The paper also illustrates the sensitivity of this O3 production/loss state to H2O and NO concentrations, photolysis rates, and temperatures.
We present examples of how chemical evolution can exhibit sensitivity to mixing arising from stratosphere‐troposphere exchange. A chemical transport model is used to survey the chemical contrasts on ...isentropic surfaces that intersect the tropopause. Significant cross‐tropopause gradients in both ozone and water vapor are shown to exist between 300 and 340 K. Back trajectories are used to confirm that air parcels with widely varying chemical properties are rapidly brought together in a typical quasi‐isentropic stratosphere‐troposphere exchange event. A two‐box model is used to investigate the chemical evolution of stratospheric and tropospheric air parcels and to determine the effect of mixing between them. Mixing of stratospheric ozone and tropospheric water vapor is shown to lead to enhanced hydroxyl (OH) radical concentrations compared with background tropospheric and stratospheric values. The oxidation of CO, methane, and higher hydrocarbons is correspondingly increased, and NOx is also lost more rapidly with faster mixing. Also, in low NOx conditions, the rate of O3 loss is found to increase with faster mixing. The consequences of this anomalous chemistry for chemical transport in stratosphere‐troposphere exchange events are discussed. It is also noted that if NOx levels in either parcel are very high initially, mixing of NOx can become more important than O3 or H2O in determining OH levels.
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3053
Background: Activation of the Wnt-β-catenin signaling pathway is associated with poor T cell infiltration of tumors. We have previously demonstrated that paracrine Wnt5a-β-catenin ...signaling is a critical trigger of dendritic cell (DC) tolerization and regulatory T cell (Treg) differentiation in the melanoma microenvironment. In a transgenic BRAF
V600E
PTEN
-/-
model, the genetic silencing of melanoma-derived Wnt5a potently enhances infiltrating CD8
+
T cell effector function and promotes responses to anti-PD-1 Ab therapy. Ipafricept (IPA) is a recombinant Wnt decoy receptor and Vantictumab (VAN) is a Fzd receptor monoclonal Ab. Both molecules inhibit Wnt-β-catenin signaling and have been well-tolerated in ongoing phase I/Ib clinical trials. We explored the ability of IPA/VAN to reverse tumor-mediated immune tolerance and enhance the efficacy of anti-PD-1 Ab immunotherapy in a pre-clinical model that closely recapitulates human melanoma. Methods: Both IPA and VAN were utilized to investigate Wnt-β-catenin inhibition as a strategy for suppressing melanoma-induced DC indoleamine 2,3-dioxygenase (IDO) expression and Treg differentiation in vitro. These agents were further tested for their ability to enhance anti-tumor T cell responses and to augment the efficacy of anti-PD-1 Ab therapy in syngeneic and autochthonous models of BRAF
V600E
PTEN
-/-
melanoma. Results: IPA and VAN effectively inhibit Wnt5a and melanoma-induced DC IDO expression and Treg differentiation in vitro. Further studies demonstrate that IPA and VAN significantly augment anti-PD-1 Ab-mediated suppression of primary and metastatic tumor progression in both syngeneic and autochthonous BRAF
V600E
PTEN
-/-
melanoma models. These anti-tumor effects correlated with suppressed IDO enzymatic activity, enhanced tumor-infiltrating CD8
+
T cell/Treg ratios, and increased activation of TRP2 antigen-specific effector T cells. Conclusions: The pharmacological inhibition of paracrine Wnt-β-catenin signaling with IPA and VAN augment the anti-tumor efficacy of anti-PD-1 Ab therapy and represent a promising strategy for further phase I testing in melanoma and other solid tumors.
The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further ...studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane–bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti–CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node–derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt–β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy.
Abstract
The pulmonary surfactant lipoprotein complex lowers the surface tension at the alveolar/airway interface of the lung and participates in pulmonary host defense. Previous studies have shown ...that surfactant protein A (SP-A) inhibits lymphocyte proliferation. We hypothesized that surfactant proteins may modulate the activation threshold of T cells depending upon the strength of the activation signal.
The strength and duration of lymphocyte activation are crucial in determining the fate of responding lymphocytes. Activation of specific signaling pathways, including NFkB, NFAT, STAT and MAPK pathways, determines the quality, magnitude and duration of immune responses, imparts a tunable quality, and essentially constitutes the 'strength of signal' (SoS). This study highlights a differential role of SP-A across multiple modes of T cell activation. Modulation of signal strength imparted by different activating agents ex vivo and in vivo in different mouse models, as well as in vitro with human cells show a strong correlation between strength of signal and functional effects of SP-A interactions. While proliferation is enhanced in the presence of SP-A at low signal strengths, the inhibition reported in the literature is observed at higher SoS. The enhanced proliferation is observed within a kinetic envelope, and is largely absent in SP-A-/- mice, while the inhibition is primarily caused by lack of cell cycle progression, with no effect on cell death or early cytokine production. This is intrinsic to the global T cell population, and is not mediated by proportions of Treg or effector memory cells. Changes in capacitative Ca++i flux are likely to be a key component of these phenotypic effects.
Support: NIH HL-68072
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