Rebalancing TGFß1/BMP signals in exhausted T cells unlocks responsiveness to immune checkpoint blockade therapy.

T cell dysfunctionality prevents the clearance of chronic infections and cancer. Furthermore, epigenetic programming in dysfunctional CD8+ T cells limits their response to immunotherapies, including immune checkpoint blockade (ICB). However, it is unclear which upstream signals drive acquisition of dysfunctional epigenetic programs, and whether therapeutically targeting these signals can remodel terminally dysfunctional T cells to an ICB-responsive state. Here we innovate an in vitro model system of stable human T cell dysfunction and show that chronic TGFß1 signaling in posteffector CD8+ T cells accelerates their terminal dysfunction through stable epigenetic changes. Conversely, boosting bone morphogenetic protein (BMP) signaling while blocking TGFß1 preserved effector and memory programs in chronically stimulated human CD8+ T cells, inducing superior responses to tumors and synergizing the ICB responses during chronic viral infection. Thus, rebalancing TGFß1/BMP signals provides an exciting new approach to unleash dysfunctional CD8+ T cells and enhance T cell immunotherapies.

Congenital Lobar Emphysema: Anaesthetic Challenges and Review of Literature.

Congenital Lobar Emphysema (CLE) is a developmental anomaly, characterized by hyperinflation of one or more pulmonary lobes. It presents in infancy with variable degree of respiratory distress due to compression atelectasis. It is most often associated with mediastinal shift with subsequent hypoxia. CLE poses a diagnostic and therapeutic dilemma. We report a case of five-month-old infant of CLE requiring left lobectomy, who was previously being treated for pneumonia which was unresponsive to medical therapy. Anaesthetic challenges experienced during the case and a brief review of literature is presented.