Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Using syngeneic immunocompetent tumor models, we reveal that in the therapeutic effects of CD47 blockade depend on dendritic cell (DC) but not macrophage cross-priming of T cell responses in immunocompetent mice. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the anti-tumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c+ cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of anti-tumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors.

Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.

No abstract

CD47 on tumor cells protects from phagocytosis, while PD-L1 dampens T cell-mediated tumor killing. However, whether and how CD47 and PD-L1 coordinate is poorly understood. We reveal that CD47 and PD-L1 on tumor cells coordinately suppress innate and adaptive sensing to evade immune control. Targeted blockade of both CD47 and PD-L1 on tumor cells with a bispecific anti-PD-L1-SIRPα showed significantly enhanced tumor targeting and therapeutic efficacy versus monotherapy. Mechanistically, systemic delivery of the dual-targeting heterodimer significantly increased DNA sensing, DC cross-presentation, and anti-tumor T cell response. In addition, chemotherapy that increases "eat me" signaling further synergizes with the bispecific reagent for better tumor control. Our data indicate that tumor cells evolve to utilize both innate and adaptive checkpoints to evade anti-tumor immune responses and that tumor cell-specific dual-targeting of both checkpoints represents an improved strategy for tumor immunotherapy.

SummaryLuo Z-C, An N, Xu H-R, Larante A, Audibert F and Fraser WD. The effects and mechanisms of primiparity on the risk of pre-eclampsia: a systematic review. Paediatric and Perinatal Epidemiology 2007; 21(Suppl. 1): 36-45.Pre-eclampsia has been dubbed as 'a disease of primiparity'. However, the effects and mechanisms of the association of primiparity with pre-eclampsia have not been clearly defined. We conducted a systematic review of studies evaluating the effect of primiparity on the risk of pre-eclampsia, and studies (published between January 1966 and July 2005) on the mechanisms underlying such an association. A total of 26 original studies were identified and a meta-analysis carried out for the risk of pre-eclampsia among primiparous vs. multiparous women.Variably (1.4-5.5 times) higher risks of pre-eclampsia were observed in primiparous women in all studies, with a summary odds ratio (OR) of 2.42 [95% CI 2.16, 2.71]. The adjusted ORs were larger than crude ORs in all but one study after various adjustments. Except for abundant epidemiological evidence in support of the immune maladaptation theory, only four original studies examined the actual mechanisms of such primiparity-associated risk. Two (small) studies suggested differences in immunological responses in the aetiology of pre-eclampsia in primiparous vs. multiparous women. Two recent studies indicated that differences in angiogenic factor profile or reactivity to insulin resistance in early pregnancy may explain the elevated pre-eclampsia risk in first pregnancies. In conclusion, primiparity is associated with approximately 2.4-fold elevated risk of pre-eclampsia. Although immune maladaptation is generally considered as the basis to explain such an elevated risk, few data are available on immune maladaptation parameters in primiparous vs. multiparous pregnancies. Available data are insufficient to interpret the mechanisms of such primiparity-associated excess risk of pre-eclampsia.

The incidence of giant cell tumor in the Chinese population may be higher than that in Western countries, and it has a male predilection. The results of the present study suggest that extensive curettage provides favorable local control and satisfactory functional outcomes.

Continuous thymic homing of haematopoietic progenitor cells (HPCs) via the blood is critical for normal T-cell development. However, the nature and the differentiation programme of specialized thymic endothelial cells (ECs) controlling this process remain poorly understood. Here using conditional gene-deficient mice, we find that lymphotoxin beta receptor (LTβR) directly controls thymic ECs to guide HPC homing. Interestingly, T-cell deficiency or conditional ablation of T-cell-engaged LTβR signalling results in a defect in thymic HPC homing, suggesting the feedback regulation of thymic progenitor homing by thymic products. Furthermore, we identify and characterize a special thymic portal EC population with features that guide HPC homing. LTβR is essential for the differentiation and homeostasis of these thymic portal ECs. Finally, we show that LTβR is required for T-cell regeneration on irradiation-induced thymic injury. Together, these results uncover a cellular and molecular pathway that governs thymic EC differentiation for HPC homing.