Anti-PD-L1 treatment to enhance the response of glioblastoma to radiation and produce long-term survival in mice.

e14048 Background: Glioblastoma (GBM) is the most aggressive and most common primary central nervous system cancer in adults. Blocking the interaction between Programmed Cell Death Protein-1 (PD-1) and its ligand (PD-L1) has shown remarkable success in the treatment of several cancers. However, many challenges remain in improving the efficacy of using monoclonal antibodies (Ab) against the receptor PD-1 in GBM, mainly due to the “non-immunogenic” tumor characteristics of GBM. PD-L1 has been found to be overexpressed on the surface of human GBM tumor cells and tumor-associated macrophages (TAM). Radiotherapy (RT), as one of the standard therapy of GBM, could alter the tumor microenvironment and promote an antitumor immune response. We hypothesize that anti-PD-L1 therapy can enhance the RT effects and improve the outcome of treatment when combined. Methods: Using a preclinical orthotropic syngeneic CT-2A mouse GBM tumor model, we studied the efficacy of combined therapy with anti-PD-L1 and RT. Mice were stratified into four treatment groups: control, RT, anti-PD-L1 Ab, and anti-PD-L1 Ab plus RT. RT(8 Gy) was given one time simultaneously with the first dose of anti-PD-L1, followed by systemic anti-PD-L1 maintenance treatment to the mice. Overall survival and tumor growth were monitored. Immunohistochemistry on resected tumors during treatment was performed to characterize the immune response. Single-cell RNA sequencing (scRNA-seq) was also performed to further study the immunologic parameters in the mouse brain. Results: Our results showed that anti-PD-L1 Ab in combination with RT provided a remarkable antitumor immune response and improved overall survival, with 25.5, 34, and 30 days of median survival in control (no-treatment), RT, and anti-PD-L1 groups, respectively, and achieving long-term survival and complete tumor response in 80% of the mice in the anti-PD-L1+RT treatment group (median survival not reached) in GBM tumor-bearing mice. The combined therapy promoted the recruitment of tumor-infiltrating immune cells, reversed the hostile tumor immune environment with a higher M1/TAM ratio, CD8+ /CD4+ T cell ratio, and CD8+ T cell /Treg cell ratio in the tumor area comparing with those parameters in single modality treatment groups. Furthermore, scRNA-seq data demonstrated that anti-PD-L1 combined with RT resulted in robust higher CD8 effector T cells, while lower CD4 and CD8 exhausted T cells in the tumor region compared to other groups. Increased CD4 central memory T cells and CD8 central memory T cells were seen only in tumors treated with anti-PD-L1+RT providing immunologic explanations on the durable control of GBM achieved only by the combined therapy. Conclusions: The anti-PD-L1 therapy synergizes with RT by reversing the hostile tumor immune environment resulting in improved tumor control and long-term survival in the syngeneic mouse GBM model.

Protracted yet coordinated differentiation of long-lived SARS-CoV-2-specific CD8+ T cells during COVID-19 convalescence

ABSTRACTCD8+ T cells are important antiviral effectors that can potentiate long-lived immunity against COVID-19, but a detailed characterization of these cells has been hampered by technical challenges. We screened 21 well-characterized, longitudinally-sampled convalescent donors that recovered from mild COVID-19 against a collection of SARS-CoV-2 tetramers, and identified one participant with an immunodominant response against Nuc322-331, a peptide that is conserved in all the SARS-CoV-2 variants-of-concern reported to date. We conducted 38- parameter CyTOF phenotyping on tetramer-identified Nuc322-331-specific CD8+ T cells, and on CD4+ and CD8+ T cells recognizing the entire nucleocapsid and spike proteins from SARS- CoV-2, and took 32 serological measurements on longitudinal specimens from this participant. We discovered a coordination of the Nuc322-331-specific CD8+ T response with both the CD4+ T cell and antibody pillars of adaptive immunity. Nuc322-331-specific CD8+ T cells were predominantly central memory T cells, but continually evolved over a ∼6-month period of convalescence. We observed a slow and progressive decrease in the activation state and polyfunctionality of the Nuc322-331-specific CD8+ T cells, accompanied by an increase in their lymph-node homing and homeostatic proliferation potential. These results suggest that following a typical case of mild COVID-19, SARS-CoV-2-specific CD8+ T cells not only persist but continuously differentiate in a coordinated fashion well into convalescence, into a state characteristic of long-lived, self-renewing memory.

Gold nanoparticles (AuNPs) impair LPS-driven immune responses by promoting a tolerogenic-like dendritic cell phenotype with altered endosomal structures

This study shows that gold nanoparticles promote the differentiation of dendritic cells to a tolerogenic-like phenotype, affecting their ability to induce antibacterial immune responses mediated by Th1 cells and to activate central memory T cells.

RESEARCH OF RESTORATION PROCESSES AFTER INDUCTION OF LYMPHOPENIA BY CYCLOPHOSPHANE IN AN EXPERIMENTAL MODEL ON MOUSE

Objective: to evaluate the dynamics of T-cell recovery after exposure to cyclophosphamide (CP). CP was injected at a dose of 125 mg/kg, followed by killing of mice on days 0, 10, 20, 30, 60 and determination of the subpopulation composition by flow cytometry. It was shown that thymocytes are more vulnerable to the action of the CP than spleen lymphocytes. Cell restoration in the thymus begins earlier with delayed recovery of spleen lymphocytes. Due to CP, there is an increase in the conversion of the naive T-cells into central memory T-cells with a relative accumulation of the latter.