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Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide–TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens ( n  = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity. Cancer vaccines that self-assemble into uniform nanoparticles improve tumor clearance.

The morphogenic process of convergent thickening (CT) was originally described as the mediolateral convergence and radial thickening of the explanted ventral involuting marginal zone (IMZ) of Xenopus gastrulae (Keller and Danilchik, 1988). Here, we show that CT is expressed in all sectors of the pre-involution IMZ, which transitions to expressing convergent extension (CE) after involution. CT occurs without CE and drives symmetric blastopore closure in ventralized embryos. Assays of tissue affinity and tissue surface tension measurements suggest CT is driven by increased interfacial tension between the deep IMZ and the overlying epithelium. The resulting minimization of deep IMZ surface area drives a tendency to shorten the mediolateral (circumblastoporal) aspect of the IMZ, thereby generating tensile force contributing to blastopore closure (Shook et al., 2018). These results establish CT as an independent force-generating process of evolutionary significance and provide the first clear example of an oriented, tensile force generated by an isotropic, Holtfreterian/Steinbergian tissue affinity change.

BackgroundImmune checkpoint blockade has shown promising antitumor activity against a variety of tumor types. However, responses in castration-resistant prostate cancer remain relatively rare—potentially due to low baseline levels of infiltration. Using an immunocompetent cMyc-driven model (Myc-CaP), we sought to understand the immune infiltrate induced by androgen deprivation therapy (ADT) and to leverage that infiltration toward therapeutic benefit.MethodsUsing flow cytometry, qPCR and IHC, we quantified ADT-induced immune infiltration in terms of cell type and function. Preclinical treatment studies tested the combinatorial effects of ADT and immune checkpoint blockade using tumor outgrowth and overall survival as end points.ResultsADT induces a complex pro-inflammatory infiltrate. This pro-inflammatory infiltrate was apparent in the early postcastration period but diminished as castration resistance emerged. Combining ADT with tumor-infiltrating regulatory T cell (Treg) depletion using a depleting anti-CTLA-4 antibody significantly delayed the development of castration resistance and prolonged survival of a fraction of tumor-bearing mice. Immunotherapy as a monotherapy failed to provide a survival benefit and was ineffective if not administered in the peri-castration period.ConclusionsThe immune infiltrate induced by ADT is diverse and varies over time. Therapeutic strategies focusing on depleting Tregs in the peri-castration period are of particular interest.

BackgroundProstaglandin E2 (PGE2) is a bioactive lipid produced by tumor cells that drives disease progression through stimulating tumor proliferation, enhancing angiogenesis and suppressing immune function in the TME.1 PGE2 is also a mediator of adaptive resistance to immune checkpoint inhibitor therapy via the upregulation of cyclooxygenase-2 (COX-2). While the role of PGE2 signaling in cancer is clear, how best to inhibit PGE2 for cancer treatment remains under investigation. Inhibition of COX-1 and/or COX-2 has shown promising results in observational studies and meta-analyses, but inconsistent results in prospective studies. PGE2 signals through four receptors, EP1-4, that are variably expressed on tumor and immune cells and have distinct biological activities. The EP2/EP4 receptors signal through cAMP and drive pro-tumor activities, while EP1/EP3 receptors signal through calcium flux and IP3 and drive immune activation and inflammation. While COX-2 and single EP inhibitors continue to be developed, the nature of PGE2 signaling supports our rationale to inhibit PGE2 by dual antagonism of the pro-tumor EP2/EP4 receptors, while sparing the pro-immune EP1/EP3 receptors.MethodsWe utilized human and murine whole blood to perform in vitro characterization of PGE2/inhibitor activity. In vivo, CT26 tumors and APCmin/+ mice were used to model CRC and measure immune endpoints.ResultsIn mouse and human whole blood assays, dual blockade of EP2 and EP4 receptors with TPST-1495 reversed PGE2-mediated suppression of LPS induced TNF-α, while EP4 receptor antagonists were unable to block suppression at higher PGE2 concentrations. Similarly, in murine and human T cells in vitro, TPST-1495 inhibited PGE2-mediated suppression, resulting in a significant increase of IFN-γ production in response to stimulation with cognate peptide Ag. In vivo, TPST-1495 therapy alone also significantly reduced tumor outgrowth in CT26 tumor bearing mice, correlated with increased tumor infiltration by NK cells, CD8+ T cells, AH1-specific CD8+ T cells, and DCs. The induced NKp46+CD4-CD8- cell population appeared to have an important role in TPST-1495 efficacy, as significant anti-tumor activity was observed in murine models lacking T Cells, particularly CT26 tumor-bearing RAG2-/- mice. TPST-1495 monotherapy demonstrated a decrease of both the intestinal tumor size and number in Adenomatous Polyposis (APCmin/+) mice, as compared to a single EP4 antagonist.ConclusionsTPST-1495 is a potent inhibitor of PGE2 mediated immune suppression and is currently being evaluated in an ongoing Phase 1 first-in-human study (NCT04344795) to characterize PK, PD, safety, and to identify a recommended phase 2 dose for expansion cohorts in key indications and biomarker selected patients.ReferenceZelenay S, van der Veen AG, Böttcher JP, et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 2015;162(6):1257–70. doi: 10.1016/j.cell.2015.08.015

BackgroundGlioblastoma (GBM) is a poorly immunogenic neoplasm treated with focused radiation. Immunotherapy has demonstrated synergistic survival effects with stereotactic radiosurgery (SRS) in murine GBM. GITR is a co-stimulatory molecule expressed constitutively on regulatory T-cells and by effector T-cells upon activation. We tested the hypothesis that anti-GITR monoclonal antibody (mAb) and SRS together would confer an immune-mediated survival benefit in glioma using the orthotopic GL261 glioma model.MethodsMice received SRS and anti-GITR 10 days after implantation. The anti-GITR mAbs tested were formatted as mouse IgG1 D265A (anti-GITR (1)) and IgG2a (anti-GITR (2a)) isotypes. Mice were randomized to four treatment groups: (1) control; (2) SRS; (3) anti-GITR; (4) anti-GITR/SRS. SRS was delivered to the tumor in one fraction, and mice were treated with mAb thrice. Mice were euthanized on day 21 to analyze the immunologic profile of tumor, spleen, and tumor draining lymph nodes.ResultsAnti-GITR (1)/SRS significantly improved survival over either treatment alone (p < .0001) with a cure rate of 24 % versus 0 % in a T-lymphocyte-dependent manner. There was elevated intratumoral CD4+ effector cell infiltration relative to Treg infiltration in mice treated with anti-GITR (1)/SRS, as well as significantly elevated IFNγ and IL-2 production by CD4+ T-cells and elevated IFNγ and TNFα production by CD8+ T-cells. There was increased mRNA expression of M1 markers and decreased expression of M2 markers in tumor infiltrating mononuclear cells. The anti-GITR (2a)/SRS combination did not improve survival, induce tumor regression, or result in Treg depletion.ConclusionsThese findings provide preclinical evidence for the use of anti-GITR (1) non-depleting antibodies in combination with SRS in GBM.

BACKGROUND: Primary prostate cancers are infiltrated with programmed death-1 (PD-1) expressing CD8+ T-cells. However, in early clinical trials, men with metastatic castrate-resistant prostate cancer did not respond to PD-1 blockade as a monotherapy. One explanation for this unresponsiveness could be that prostate tumors generally do not express programmed death ligand-1 (PD-L1), the primary ligand for PD-1. However, lack of PD-L1 expression in prostate cancer would be surprising, given that phosphatase and tensin homolog (PTEN) loss is relatively common in prostate cancer and several studies have shown that PTEN loss correlates with PD-L1 upregulation—constituting a mechanism of innate immune resistance. This study tested whether prostate cancer cells were capable of expressing PD-L1, and whether the rare PD-L1 expression that occurs in human specimens correlates with PTEN loss. METHODS: Human prostate cancer cell lines were evaluated for PD-L1 expression and loss of PTEN by flow cytometry and western blotting, respectively. Immunohistochemical (IHC) staining for PTEN was correlated with PD-L1 IHC using a series of resected human prostate cancer samples. RESULTS: In vitro , many prostate cancer cell lines upregulated PD-L1 expression in response to inflammatory cytokines, consistent with adaptive immune resistance. In these cell lines, no association between PTEN loss and PD-L1 expression was apparent. In primary prostate tumors, PD-L1 expression was rare, and was not associated with PTEN loss. CONCLUSIONS: These studies show that some prostate cancer cell lines are capable of expressing PD-L1. However, in human prostate cancer, PTEN loss is not associated with PD-L1 expression, arguing against innate immune resistance as a mechanism that mitigates antitumor immune responses in this disease.

[This corrects the article DOI: 10.1186/s40425-016-0132-2.].

One of the current questions surrounding CD4 T regulatory cells (Tregs) is the role of natural and induced Tregs in tumor tolerance. Natural Tregs are CD4 T cells that leave the thymus expressing FoxP3 and displaying regulatory potential. Induced Tregs leave the thymus as a naïve CD4 T cell (FoxP3-), but are skewed by conditions encountered during antigen recognition to express FoxP3 and gain regulatory function. Several groups have recently suggested that Neuropilin-1 may be a suitable marker for natural Tregs. To examine the ability of neuropilin-1 to identify natural versus in vivo induced Tregs, we bred a CD4 T cell receptor transgenic mouse specific for HA (6.5) onto a Rag-2 -/- background. The resultant 6.5 Rag -/- mice have no Tregs (as defined by FoxP3 expression), as has been noted for other TCR transgenic models, and express no neuropilin-1 (or CD25) prior to manipulation. To test whether neuropilin-1 was expressed on in vivo induced Tregs we performed a series of adoptive transfer studies into A) non-transgenic hosts, followed by low dose i.v. HA peptide administration B) self antigen expressing animals (C3-HAlow) or C) tumor antigen expressing mice (established HA expressing 4T1 mammary carcinomas). Our data show that in vivo induced Tregs clearly express neuropilin-1 under these various conditions. Furthermore, neuropilin-1 expression was found on both FoxP3+ and FoxP3- populations in all three models of in vivo induced Tregs, suggesting that neuropilin-1 is expressed on activated cells. Consistent with this notion, we found that neuropilin-1 was strongly upregulated within the first several divisions on 6.5 CD4 T cells when adoptively transferred into a host receiving HA expressing Vaccinia Virus. CD25 expression was more closely associated with FoxP3 expression than neuropilin-1: In the low dose i.v. peptide model, neuropilin-1+ CD25+ 6.5 CD4 T cells were significantly enriched for FoxP3 and Helios expression, whereas neuropilin-1+ CD25- 6.5 CD4 T cells were not. Tumor induced 6.5 CD4 Tregs also expressed low levels of neuropilin-1, even though the majority of 6.5 CD4 T cells were not induced to express FoxP3 by tumor antigen recognition. These data strongly support the notion that neuropilin-1 is not a specific marker of natural Tregs in mice, and further suggest that the majority of FoxP3+ TILS are likely natural Tregs, rather than induced Tregs.