Lindbartlett9485

structures; GC germinal center(s); PDAC pancreatic ductal adenocarcinoma; RNA-seq RNA sequencing; BCRseq B cell receptor sequencing; HEV high endothelial venule; PNAd peripheral node addressin; TMB tumor mutational burden; TCGA the cancer genome atlas; PAAD pancreatic adenocarcinoma; FFPE formalin fixed paraffin embedded; TIME tumor immune microenvironment.Immunotherapy via interleukin-2 (IL-2) mediated activation of anti-tumor immune response is a promising approach for cancer treatment. The multi-potent cytokine, IL-2 has a central role in immune cell activation and homeostasis. Since IL-2 preferentially activates immunosuppressive T regulatory cells by IL-2Rα dependent manner, blocking IL-2IL-2Rα interaction is a key to amplify the IL-2 activity in effector T cells toward anti-tumor response. Anti-IL-2 monoclonal antibodies are good candidates to control the IL-2IL-2Rα interaction. In a previous study, we developed a new IL-2Rα mimetic antibody, TCB2, and showed that the human IL-2(hIL-2)TCB2 complex can stimulate T effector cells specifically and elicit potent anti-cancer immunotherapeutic effect, especially when administered in combination with immune checkpoint inhibitors. To understand the molecular mechanism, we determined the crystal structure of TCB2-Fab in a complex with hIL-2 at 2.5 Å resolution. Our structural analysis reveals that TCB2 binds to the central area of the hIL-2Rα binding region on hIL-2, and binding angle and epitope are different from previously known hIL-2Rα mimicking antibody NARA1 which recognizes the top part of hIL-2. TCB2 binding to hIL-2 also induces an allosteric effect that increases the affinity for the hetero-dimeric hIL-2 receptor, IL-2R(β + γ), on effector T cells.An indicator for systemic evaluation of the adaptive immune status is lacking. Peripheral blood is important in antitumour immunity, and the T-cell receptor (TCR) repertoire diversity is key for effective immunity. This study aimed to investigate changes in the circulating T cell receptor β chain (TCRB) diversity during the first few (1 ~ 4) treatment cycles and its clinical value in patients with advanced lung cancer. TCRB-enriched sequencing data combined with transcriptomic RNA sequencing data of peripheral blood leukocytes were obtained from 72 patients with advanced lung cancer before and after targeted therapy or chemotherapy. Changes in the circulating TCRB diversity during treatment and the relationship of the baseline circulating TCRB diversity with prognosis and therapeutic effects were evaluated. We found that targeted therapy or chemotherapy did not significantly affect the T lymphocyte composition or circulating TCRB diversity (3.83 vs 3.74, T-test, p = .16) in patients with advanced lung adenocarcinoma (LUAD) during the first few treatment cycles. click here The higher circulating TCRB diversity was linked to improved therapeutic effects (T-test, p = .00083) in LUAD patients receiving targeted therapy. Higher baseline circulating TCRB diversity was associated with better prognosis. In addition, a five-factor prognostic risk score model was built for more accurate prognosis prediction for LUAD patients. The chemotherapeutic agents for advanced lung cancer do not significantly affect adaptive immune function over the first few treatment cycles. The circulating TCRB diversity reflects the adaptive immunological repertoire and might be a convenient indicator for evaluating the adaptive immune status and prognosis.Targeted immunotherapy of solid cancers with chimeric antigen receptor (CAR) T cells and immunocytokines are attractive options in that they both rely on the specificity of tumor-targeted antibodies. Since carcinoembryonic antigen (CEA) expression in both colon and breast cancers is correlated with poor prognosis, it was chosen as a model tumor target in immunocompetent CEA transgenic (CEATg) mice. A second-generation anti-CEA CAR derived from CEA-specific antibody T84.66 was used to treat murine MC38 colon or E0771 breast carcinomas transfected with CEA. Anti-CEA CAR vs. mock transduced T cells exhibited a CEA-specific cytotoxic and IFN γ dose response to both CEA transfected cell lines vs. their CEA-negative controls. Anti-CEA CAR vs. mock transduced T cells delayed the median survival of CEA transfected s.c. MC38 or orthotopic E0771 tumor-bearing CEATg mice by 2 days. With the addition of one-day prior cyclophosphamide (CY) lymphodepletion, anti-CEA CAR T cell treatment delayed the median survival of MC38/CEA and E0771/CEA tumor-bearing CEATg mice by ten and 3 days, respectively. Since CAR T cells require IL2 for survival and expansion, anti-CEA-IL2 immunocytokine (ICK) treatment was performed post CAR T cell therapy. Single ICK treatment 1 day after CY plus anti-CEA CAR T cell therapy in the MC38/CEA model, and two ICK treatments every 3 days after CY plus anti-CEA CAR T cell therapy in the E0771/CEA model were ineffective, while four ICK treatments every 3 days after CY plus anti-CEA CAR T cell therapy completely eradicated MC38/CEA tumor growth and induced tumor immunity when the mice were re-challenged with tumor. These studies show the therapeutic potential of anti-CEA CAR T cells combined with ICK to treat CEA-positive tumors. Abbreviations CAR Chimeric antigen receptor, CEA Carcinoembryonic antigen, CEACAM5, ICK Immunocytokine, CY Cyclophosphamide, CEATg mouse transgenic CEA mouse, TDLN Tumor-draining lymph node.Cancer is a heterogeneous disease and its treatment remains unsatisfactory with inconstant therapeutic responses. This variability could be related, at least in part, to different and highly personalized gut microbiota compositions. Different studies have shown an impact of microbiota on antitumor therapy. It has been demonstrated that some gut bacteria influences the development and differentiation of immune cells, suggesting that different microbiota compositions could affect the efficacy of the antitumor vaccine. Emerging data suggest that recognition of neoantigens for the generation of neoantigen cancer vaccines (NCVs) could have a key role in the activity of clinical immunotherapies. However, it is still unknown whether there is a crosstalk between microbiota and NCV. This study aimed to understand the possible mechanisms of interaction between gut microbiota and NCV delivered by DNA-electroporation (DNA-EP). We found that decreased microbiota diversity induced by prolonged antibiotic (ATB) treatment is associated with higher intratumor specific immune responses and consequently to a better antitumor effect induced by NCV delivered by DNA-EP.