Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitumor immune responses

Although radiotherapy has been used for over a century to locally control tumor growth, alone it rarely induces an abscopal response or systemic antitumor immunity capable of inhibiting distal tumors outside of the irradiation field. Results from recent studies suggest that combining immune checkpoint blockades to radiotherapy may enhance abscopal activity. However, the treatment conditions and underlying immune mechanisms that consistently drive an abscopal response during radiation therapy combinations remain unknown. Here, we analyzed the antitumor responses at primary and distal tumor sites, demonstrating that the timing of αPD-1 antibody administration relative to radiotherapy determined the potency of the induced abscopal response. Blockade of the PD-1 pathway after local tumor irradiation resulted in the expansion of polyfunctional intratumoral CD8+ T cells, a decrease in intratumoral dysfunctional CD8+ T cells, expansion of reprogrammable CD8+ T cells, and induction of potent abscopal responses. However, administration of αPD-1 before irradiation almost completely abrogated systemic immunity, which associated with increased radiosensitivity and death of CD8+ T cells. The subsequent reduction of polyfunctional effector CD8+ T cells at the irradiated tumor site generated a suboptimal systemic antitumor response and the loss of abscopal responses. Therefore, this report maximizes the potential synergy between radiotherapy and αPD-1 immunotherapy, information that will benefit clinical combinations of radiotherapy and immune checkpoint blockade.

Activatable polymer nanoagonist for second near-infrared photothermal immunotherapy of cancer

Nanomedicine in combination with immunotherapy offers opportunities to treat cancer in a safe and effective manner; however, remote control of immune response with spatiotemporal precision remains challenging. We herein report a photothermally activatable polymeric pro-nanoagonist (APNA) that is specifically regulated by deep-tissue-penetrating second near-infrared (NIR-II) light for combinational photothermal immunotherapy. APNA is constructed from covalent conjugation of an immunostimulant onto a NIR-II semiconducting transducer through a labile thermo-responsive linker. Upon NIR-II photoirradiation, APNA mediates photothermal effect, which not only triggers tumor ablation and immunogenic cell death but also initiates the cleavage of thermolabile linker to liberate caged agonist for in-situ immune activation in deep solid tumor (8 mm). Such controlled immune regulation potentiates systemic antitumor immunity, leading to promoted cytotoxic T lymphocytes and helper T cell infiltration in distal tumor, lung and liver to inhibit cancer metastasis. Thereby, the present work illustrates a generic strategy to prepare pro-immunostimulants for spatiotemporal regulation of cancer nano-immunotherapy.

Exosome-Transmitted lncRNA H19 Inhibits the Growth of Pituitary Adenoma

Context Our previous study demonstrated that the expression of long noncoding RNA (lncRNA) H19 was frequently downregulated in human primary pituitary adenomas and negatively correlated with tumor progression. However, the role of exosomal lncRNA H19 in the inhibition of pituitary tumor growth remains unclear. Objective To investigate whether exosomal H19 could be transported across the cell membrane to exert its inhibitory effect on pituitary tumor growth. Design Empty lentivirus GH3 cells with or without H19 overexpression were used to establish a xenograft model. Isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking, and Western blotting. The expression levels of serum exosomal H19 from 200 healthy subjects and 206 patients with various subtypes of pituitary tumors were detected by ultracentrifugation and quantitative real-time PCR. Results The growth of distal tumor cells was inhibited by transferring exosomal H19, which could be transported through cell membrane and exert its inhibitory effect. Cabergoline increased H19 expression and played a synergic therapeutic effect with exosomal H19. Exosomal H19 inhibited phosphorylation of the mTORC1 substrate 4E-BP1. Of note, the expression level of exosomal H19 in the patients with all subtypes of pituitary tumors was significantly lower than that in the healthy subjects. The change of plasma exosomal H19 level may be correlated with the prognosis or drug response of the patients. Conclusion Exosomal H19 inhibits the growth of distal pituitary tumors through inhibiting 4E-BP1 phosphorylation. Plasma exosomal H19 may serve as an important biomarker for predicting medical responses of patients with prolactinomas.

Immunobiochemical reconstruction of influenza lung infection - Melanoma skin cancer interactions

Our recent experimental results that combine a mouse model of influenza A virus (IAV) infection (A/H1N1/PR8) and a highly aggressive model of infection-unrelated cancer, B16-F10 skin melanoma, showed that acute influenza infection of the lung promotes distal melanoma growth in the dermis of the flank and leads to decreased host survival. Here, we proceed to ground the experimental observations in a mechanistic immunobiochemical model that incorporates the T cell receptor signaling pathway, various transcription factors, and a gene regulatory network (GRN). A core component of our model is a biochemical motif, which we call a Triple Incoherent Feed-Forward Loop (TIFFL), and which reflects known interactions between IRF4, Blimp-1, and Bcl-6. The different activity levels of the TIFFL components, as a function of the cognate antigen levels and the given inflammation context, manifest themselves in phenotypically distinct outcomes. Specifically, both the TIFFL reconstruction and quantitative estimates obtained from the model allowed us to formulate a hypothesis that it is the loss of the fundamental TIFFL-induced adaptation of the expression of PD-1 receptors on anti-melanoma CD8+ T cells that constitutes the essence of the previously unrecognized immunologic factor that promotes the experimentally observed distal tumor growth in the presence of acute non-ocogenic infection. We therefore hope that this work can further highlight the importance of adaptive mechanisms by which immune functions contribute to the balance between self and non-self immune tolerance, adaptive resistance, and the strength of TCR-induced activation, thus contributing to the understanding of a broader complexity of fundamental interactions between pathogens and tumors.

SOME FEATURES OF CHOLESTASIS IN CANCER PATIENTS DURING THE REDUCTION OF LIVER FUNCTIONAL RESERVES

Purpose. To determine the indications for the supra - and transpapillary externally-internal drainaging of the biliary tree in case of jaundice syndrome. Material and methods. The results of minimally invasive treatment of 246 patients with external-internal drainage of the biliary tree were analyzed. Among patients with proximal tumor block the external-internal drainage is made in 92 cases, in 42 (45,7%) out of them in suprapapillary embodiment and in 50 (54,3%) - via transpapillary approach. In 154 cases with distal tumor (obstruction peripapillary cancer) transpapillary drainage was performed. Results. The technical success of the external-internal drainaging was achieved in 242 patients (98,4%). It was failed to pass the duodenum in 4 patients with the cancer of common bile duct (3) and cancer of papilla of Vater (1). There was no complications related to the technique of external-internal drainage. In 18 patients (8,8%) out of 204 with transpapillary location of the drainage, we were forced to temporarily return to full outer bile outflow because of acute cholangitis. The syndrome of an acute blockade of the papilla of Vater arising after transpapillary external-internal drainaging required endoscopic papillosphincterotomy in 42 (84%) out of 50 patients with proximal tumor block bile outflow and in 7 (4.5%) out of 154 patients with peripapillary cancer. Conclusion. Suprapapillary and transpapillary embodiment of the drainage are equivalent in terms of the efficacy of cholestasis elimination. Syndrome of an acute blockade of papilla of Vater is the most often complication of the transpapillary external-internal drainage requiring the carrying out of endoscopic papillotomy «on drainage». This syndrome arises very frequently in a case of transpapillary external-internal drainage due to the proximal tumor obstruction of the biliary tree. The risk of acute cholangitis due to regurgitation after manipulation is absent in the suprapapillary location of the external-internal drainage, and with its transpapillary position is realized only with a concomitant violation of the outflow of bile.

Preoperative endovascular embolization of meningiomas: update on therapeutic options

In this review paper the authors analyze new therapeutic options for the embolization of meningiomas, as well as the future of meningioma treatment through recent relevant cohorts and articles. They investigate various embolic materials, types of meningiomas amenable to embolization, imaging techniques, and potential imaging biomarkers that could aid in the delivery of embolic materials. They also analyze perfusion status, complications, and new technical aspects of endovascular preoperative embolization of meningiomas. A literature search was performed in PubMed using the terms “meningioma” and “embolization” to investigate recent therapeutic options involving embolization in the treatment of meningioma. The authors looked at various cohorts, complications, materials, and timings of meningioma treatment. Liquid embolic materials are preferable to particle agents because particle embolization carries a higher risk of hemorrhage. Liquid agents maximize the effect of devascularization because of deeper penetration into the trunk and distal tumor vessels. The 3 main imaging techniques, MRI, CT, and angiography, can all be used in a complementary fashion to aid in analyzing and treating meningiomas. Intraarterial perfusion MRI and a new imaging modality for identifying biomarkers, susceptibility-weighted principles of echo shifting with a train of observations (SW-PRESTO), can relay information about perfusion status and degrees of ischemia in embolized meningiomas, and they could be very useful in the realm of therapeutics with embolic material delivery. Direct puncture is yet another therapeutic technique that would allow for more accurate embolization and less blood loss during resection.