Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells.

Regulatory T (T) cells have an immunosuppressive function and highly express the immune checkpoint receptor PD-1 in the tumor microenvironment; however, the function of PD-1 in tumor-infiltrating (TI) T cells remains controversial. Here, we showed that conditional deletion of PD-1 in T cells delayed tumor progression. In Pdcd1Foxp3 mice, in which both PD-1-expressing and PD-1-deficient T cells coexisted in the same tissue environment, conditional deletion of PD-1 in T cells resulted in impairment of the proliferative and suppressive capacity of TI T cells.

Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 cell pulmonary influx.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is often exacerbated upon coinfection, but the underlying immunological mechanisms remain unclear. Here, to elucidate these mechanisms, we use an Mtb and lymphocytic choriomeningitis virus coinfection model. Viral coinfection significantly suppresses Mtb-specific IFN-γ production, with elevated bacterial loads and hyperinflammation in the lungs.

Establishment of a mechanism-based in vitro coculture assay for evaluating the efficacy of immune checkpoint inhibitors.

Cancer immunotherapy, which blocks immune checkpoint molecules, is an effective therapeutic strategy for human cancer patients through restoration of tumor-infiltrating (TI) cell function. However, evaluating the efficacy of immune checkpoint inhibitors (ICIs) is difficult because no standard in vitro assay for ICI efficacy evaluation exists. Additionally, blocking a particular immune checkpoint receptor (ICR) is insufficient to restore T cell functionality, because other ICRs still transduce inhibitory signals.

Differential Role of PD-1 Expressed by Various Immune and Tumor Cells in the Tumor Immune Microenvironment: Expression, Function, Therapeutic Efficacy, and Resistance to Cancer Immunotherapy.

In the tumor immune microenvironment (TIME), tumor cells interact with various cells and operate various strategies to avoid antitumor immune responses. These immune escape strategies often make the TIME resistant to cancer immunotherapy. Neutralizing immune escape strategies is necessary to overcome resistance to cancer immunotherapy.

Combination of PD-L1 and PVR determines sensitivity to PD-1 blockade.

Expression of immune checkpoint ligands (ICLs) is necessary to trigger the inhibitory signal via immune checkpoint receptors (ICRs) in exhausted T cells under tumor immune microenvironment. Nevertheless,to our knowledge, ICL expression profile in cancer patients has not been investigated. Using previously reported RNA-seq data sets, we found that expression of ICLs was patient specific but their coexpression can be patterned in non-small-cell lung cancers (NSCLCs).

Sustained Type I Interferon Reinforces NK Cell-Mediated Cancer Immunosurveillance during Chronic Virus Infection.

The importance of natural killer (NK) cells in the early immune response to viral or bacterial infection is well known. However, the phenotype, function, and physiologic role of NK cells during the late stage of persistent viral infection have not been extensively studied. Here, we characterized NK cells in mice persistently infected with lymphocytic choriomeningitis virus clone 13 and showed that in contrast to NK cells from acutely infected or uninfected mice, NK cells from chronically infected mice expressed a terminally differentiated phenotype, stronger cytotoxicity, and reduced inhibitory receptor expression.