Pivotal antitumor role of the immune checkpoint molecule B7-H1 in pancreatic cancer.

Immune checkpoint molecule B7-H1 plays a decisive immune regulatory role in different pathologies including cancer, and manipulation of B7-H1 expression became an attractive approach in cancer immunotherapy. Pancreatic cancer (PDAC) is characterized by pronounced immunosuppressive environment and B7-H1 expression correlates with PDAC prognosis. However, the first attempts to diminish B7-H1 expression in patients were not so successful. This points the complicity of PDAC immunosuppressive network and requires further examinations. We investigated the effect of B7-H1 deficiency in PDAC. Our results clearly show that partial or complete B7-H1 inhibition in vivo let to reduced tumor volume and improved survival of PDAC-bearing mice. This oncological benefit is due to the abrogation of immunosuppression provided by MDSC, macrophages, DC and Treg, which resulted in simultaneous restoration of anti-tumor immune response, namely improved accumulation and functionality of effector-memory CD4 and CD8 T cells. Our results underline the potential of B7-H1 molecule to control immunosuppressive network in PDAC and provide new issues for further clinical investigations.

Impact of 18F-FET PET/MRI on Clinical Management of Brain Tumor Patients.

Multiparametric PET/MRI with the amino-acid analog O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) enables the simultaneous assessment of molecular, morphologic, and functional brain tumor characteristics. Although it is considered the most accurate noninvasive approach in brain tumors, its relevance for patient management is still under debate. Here, we report the diagnostic performance of 18F-FET PET/MRI and its impact on clinical management in a retrospective patient cohort. Methods: We retrospectively analyzed brain tumor patients who underwent 18F-FET PET/MRI between 2017 and 2018. 18F-FET PET/MRI examinations were indicated clinically because of equivocal standard imaging results or the clinical course. Histologic confirmation or clinical and standard imaging follow-up served as the reference standard. We evaluated 18F-FET PET/MRI accuracy in identifying malignancy in untreated suspected lesions (category, new diagnosis) and true progression during adjuvant treatment (category, detection of progression) in a clinical setting. Using multiple regression, we also estimated the contribution of single modalities to produce an optimal PET/MRI outcome. We assessed the recommended and applied therapies before and after 18F-FET PET/MRI and noted whether the treatment changed on the basis of the 18F-FET PET/MRI outcome. Results: We included 189 patients in the study. 18F-FET PET/MRI allowed the identification of malignancy at new diagnosis with an accuracy of 85% and identified true progression with an accuracy of 93%. Contrast enhancement, 18F-FET PET uptake, and tracer kinetics were the major contributors to an optimal PET/MRI outcome. In the previously equivocal patients, 18F-FET PET/MRI changed the clinical management in 33% of the untreated lesions and 53% of the cases of tumor progression. Conclusion: Our results suggest that 18F-FET PET/MRI helps clarify equivocal conditions and profoundly supports the clinical management of brain tumor patients. The optimal modality setting for 18F-FET PET/MRI and the clinical value of a simultaneous examination need further exploration. At a new diagnosis, multiparametric 18F-FET PET/MRI might help prevent unnecessary invasive procedures by ruling out malignancy; however, adding static 18F-FET PET to an already existing MRI examination seems to be of equal value. At detection of progression, multiparametric 18F-FET PET/MRI may increase therapy effectiveness by distinguishing between tumor progression and therapy-related imaging alterations.

Characterization of myeloid leukocytes and soluble mediators in pancreatic cancer: importance of myeloid-derived suppressor cells.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. PDAC cells activate tumor-specific immune responses but simultaneously trigger a strong immunosuppression. We showed that PDAC cells produce high amount of chronic inflammatory mediators and PDAC tumors build an immunosuppressive cytokine milieu, which correlates with tumor progression. We observed a low frequency of dendritic cells (DC) and a pronounced accumulation of macrophages and myeloid-derived suppressor cells (MDSC) in murine PDAC tumors. A strong accumulation of MDSC has also been demonstrated in the peripheral blood of resected PDAC patients. While DC and macrophages seem not to play a significant role in this PDAC model in the context of immunosuppression, MDSC are highly suppressive, and their accumulation is associated with an increase in intratumoral VEGF concentration during the PDAC progression. Application of the phosphodiesterase-5 inhibitor sildenafil led to a prolonged survival of PDAC-bearing female mice, which was due to the decrease in MDSC frequencies and in the systemic VEGF level. This led to a restoration of anticancer immune responses, manifested in the recovery of T lymphocyte functions and in an increase in the frequency of conventional CD4+ T cells in tumors and IFNγ level in serum of PDAC-bearing mice. Thus, MDSC are strongly involved in the PDAC-associated immunosuppression and that their depletion could create new approaches for therapy of PDAC.

Immunological in vivo effects of B7-H1 deficiency.

B7-H1 regulatory protein, a member of the B7-H family, plays a crucial role in the modulation of immune response in healthy steady-state conditions as well as in different pathologies. B7-H1 knockout mice represent an important model to elucidate further molecular and cellular mechanisms involved, among others, in autoimmunity development and cancer progression. However, a deep immunologic characterization of this model is not complete yet. This study examined the role of B7-H1 in vivo further by direct comparison of specifically phenotyped spleen immune-cell subpopulations and their activation and naïve/memory state as well as cytokine profile in wild-type and B7-H1 knockout mice. Our results demonstrated that B7-H1 deficiency in vivo modulates several immunological parameters, including the amount and composition of Gr1(+)CD11b(+) myeloid population, the composition and activation state of the DC compartment, the frequency and status of NK and NKT cells, B-cells, naïve/memory state of CD8 T-cells and production of IL-2 and IL-10 cytokines. Moreover, we observed an increase in the PD-1 expression in the immune cells in B7-H1 knockout mice compared to the wild-type animals. Valuing the importance of B7-H1 knockout mice for their use in disease models, these data underline the role of B7-H1 in vivo also in healthy state and should be taken into account in future studies on this immunosuppressive molecule.

A single M protein mutation affects the acid inactivation threshold and growth kinetics of a chimeric flavivirus.

Numerous viruses of the Flaviviridae family, including dengue, yellow fever, Japanese encephalitis, and West Nile, cause significant disease in humans and animals. The structure and function of the molecular components of the flavivirus envelope are therefore of significant interest. To our knowledge, a membrane (M) protein mutation which affects the pH at which flavivirus particles are inactivated in vitro has never been reported. Here we show that substitution of proline for glutamine at residue M5 (MQ5P) of a Japanese encephalitis-yellow fever chimera (ChimeriVax-JE) increases its acid sensitivity in vitro by 0.3 pH units (i.e., increases the pH at which virus titer is reduced by 50% from 6.08 to 6.38). In addition, growth kinetics of this mutant virus are accelerated in Vero cells, while neurovirulence and neuroinvasiveness measured in a mouse model are unaffected. A possible interpretation of these observations is that M can modulate the envelope (E) protein function during cell infection.