Harnessing IL-2 for immunotherapy against cancer and chronic infection: a historical perspective and emerging trends.

IL-2 therapy, which enhances the function of CD8 + T cells, was initially employed as the cornerstone of immunotherapy against cancer. However, the impact of this therapy extends beyond CD8 + T cells to cells expressing IL-2R, such as endothelial cells and regulatory T cells (Tregs), resulting in various side effects. Consequently, IL-2 therapy has taken a step back from the forefront of treatment.

Characteristics and anatomic location of PD-1TCF1 stem-like CD8 T cells in chronic viral infection and cancer.

CD8 T cells play an essential role in antitumor immunity and chronic viral infections. Recent findings have delineated the differentiation pathway of CD8 T cells in accordance with the progenitor-progeny relationship of TCF1 stem-like and Tim-3TCF1 more differentiated T cells. Here, we investigated the characteristics of stem-like and differentiated CD8 T cells isolated from several murine tumor models and human lung cancer samples in terms of phenotypic and transcriptional features as well as their location compared to virus-specific CD8 T cells in the chronically lymphocytic choriomeningitis virus (LCMV)-infected mice.

Defining a TCF1-expressing progenitor allogeneic CD8 T cell subset in acute graft-versus-host disease.

Graft-versus-host disease (GvHD) is a severe complication of hematopoietic stem cell transplantation driven by activated allogeneic T cells. Here, we identify a distinct subset of T cell factor-1 (TCF1) CD8 T cells in mouse allogeneic and xenogeneic transplant models of acute GvHD. These TCF1 cells exhibit distinct characteristics compared to TCF1 cells, including lower expression of inhibitory receptors and higher expression of costimulatory molecules.

IL-15 promotes self-renewal of progenitor exhausted CD8 T cells during persistent antigenic stimulation.

In chronic infections and cancer, exhausted CD8 T cells exhibit heterogeneous subpopulations. TCF1+PD-1+ progenitor exhausted CD8 T cells (Tpex) can self-renew and give rise to Tim-3+PD-1+ terminally differentiated CD8 T cells that retain their effector functions. Tpex cells are thus essential to maintaining a pool of antigen-specific CD8 T cells during persistent antigenic stimulation, and only they respond to PD-1-targeted therapy.

The impact of cancer cachexia on gut microbiota composition and short-chain fatty acid metabolism in a murine model.

This study investigates the relationship between cancer cachexia and the gut microbiota, focusing on the influence of cancer on microbial composition. Lewis lung cancer cell allografts were used to induce cachexia in mice, and body and muscle weight changes were monitored. Fecal samples were collected for targeted metabolomic analysis for short chain fatty acids and microbiome analysis.

Expression and function of CD51 on CD8 T cells as an immunomodulatory target.

T cell responses are regulated by co-stimulatory and inhibitory receptors along with T cell receptor- and cytokine-mediated signals. CD51 is a transmembrane glycoprotein of the integrin family that plays a role in cell adhesion, migration, tumorigenesis, and other cellular functions. In this study, we aimed to investigate the expression and function of CD51 on CD8 T cells.

Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation.

Brown adipose tissue (BAT) plays a pivotal role in maintaining body temperature and energy homeostasis. BAT dysfunction is associated with impaired metabolic health. Here, we show that Ssu72 phosphatase is essential for mRNA translation of genes required for thermogenesis in BAT.

PD-1 combination therapy with IL-2 modifies CD8 T cell exhaustion program.

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1TCF1 stem-like CD8 T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8 T cells that resemble highly functional effector CD8 T cells seen after an acute viral infection.

Comparison of Virulence between Two Main Clones (ST11 and ST307) of Isolates from South Korea.

In this study, we investigate the characteristics of two main clones of carbapenemase-producing isolates from South Korea, ST11 and ST307, including carbapenem-susceptible isolates. Antibiotic susceptibility, serotype or allelic type, the presence of virulence genes, and virulence with respect to serum resistance and macrophage internalization were determined for ST11 and ST307 isolates. ST11 isolates had a wide range of characteristics, including serotype and virulence, compared with those of homogeneous ST307 isolates.

Functional HPV-specific PD-1 stem-like CD8 T cells in head and neck cancer.

T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer. Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.

Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy.

Background: Radiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (abscopal effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) stimulated antitumor immune response. Here, we investigated whether the LN is also important in mediating a RT alone stimulated abscopal response.

T Cell Receptor Diversity and Lineage Relationship between Virus-Specific CD8 T Cell Subsets during Chronic Lymphocytic Choriomeningitis Virus Infection.

Recent studies on chronic viral infections have defined a novel programmed cell death 1-positive (PD-1) T cell factor 1-positive (TCF1) stem-like CD8 T cell subset that gives rise to the terminally differentiated exhausted CD8 T cells. In this study, we performed T cell receptor beta (TCRβ) sequencing of virus-specific CD8 T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection to examine the TCR diversity and lineage relationship of these two functionally distinct subsets. We found that >95% of the TCR repertoire of the exhausted CD8 T cell subset was shared with the stem-like CD8 T cells.

Re-defining T-Cell Exhaustion: Subset, Function, and Regulation.

Acute viral infection or vaccination generates highly functional memory CD8 T cells following the Ag resolution. In contrast, persistent antigenic stimulation in chronic viral infection and cancer leads to a state of T-cell dysfunction termed T-cell exhaustion. We and other have recently identified a novel subset of exhausted CD8 T cells that act as stem cells for maintaining virus-specific CD8 T cells in a mouse model of chronic lymphocytic choriomeningitis virus infection.

PD-1+ stemlike CD8 T cells are resident in lymphoid tissues during persistent LCMV infection.

The migratory patterns of virus-specific CD8 T cells during chronic viral infection are not well understood. To address this issue, we have done parabiosis experiments during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. We found that despite the high frequency of virus-specific CD8 T cells in both lymphoid and nonlymphoid tissues there was minimal migration of virus-specific CD8 T cells between the chronically infected conjoined parabiont mice.

An intra-tumoral niche maintains and differentiates stem-like CD8 T cells.

Tumour-infiltrating lymphocytes are associated with a survival benefit in several tumour types and with the response to immunotherapy. However, the reason some tumours have high CD8 T cell infiltration while others do not remains unclear. Here we investigate the requirements for maintaining a CD8 T cell response against human cancer.

Proliferating Transitory T Cells with an Effector-like Transcriptional Signature Emerge from PD-1 Stem-like CD8 T Cells during Chronic Infection.

T cell dysfunction is a characteristic feature of chronic viral infection and cancer. Recent studies in chronic lymphocytic choriomeningitis virus (LCMV) infection have defined a PD-1 Tcf-1 CD8 T cell subset capable of self-renewal and differentiation into more terminally differentiated cells that downregulate Tcf-1 and express additional inhibitory molecules such as Tim3. Here, we demonstrated that expression of the glycoprotein CD101 divides this terminally differentiated population into two subsets.

Epigenetic signature of PD-1+ TCF1+ CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade.

We have recently defined a novel population of PD-1 (programmed cell death 1)+ TCF1 (T cell factor 1)+ virus-specific CD8 T cells that function as resource cells during chronic LCMV infection and provide the proliferative burst seen after PD-1 blockade. Such CD8 T cells have been found in other chronic infections and also in cancer in mice and humans. These CD8 T cells exhibit stem-like properties undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells.

CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions.

Antigen-specific CD8 T cells are central to the control of chronic infections and cancer, but persistent antigen stimulation results in T cell exhaustion. Exhausted CD8 T cells have decreased effector function and proliferative capacity, partly caused by overexpression of inhibitory receptors such as programmed cell death (PD)-1. Blockade of the PD-1 pathway has opened a new therapeutic avenue for reinvigorating T cell responses, with positive outcomes especially for patients with cancer.

Cytokine-Mediated Regulation of CD8 T-Cell Responses During Acute and Chronic Viral Infection.

The common γ-chain cytokines, interleukin (IL)-2, IL-7, and IL-15, regulate critical aspects of antiviral CD8 T-cell responses. During acute infections, IL-2 controls expansion and differentiation of antiviral CD8 T cells, whereas IL-7 and IL-15 are key cytokines to maintain memory CD8 T cells long term in an antigen-independent manner. On the other hand, during chronic infections, in which T-cell exhaustion is established, precise roles of these cytokines in regulation of antiviral CD8 T-cell responses are not well defined.

Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice.

Adenovirus serotype 5 (Ad5) is one of the most widely used viral vectors and is known to generate potent T cell responses. While many previous studies have characterized Ad5-induced CD8 T cell responses, there is a relative lack of detailed studies that have analyzed CD4 T cells elicited by Ad5 vaccination. Here, we immunized mice with Ad5 vectors encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) and examined GP-specific CD4 T cell responses elicited by Ad5 vectors and compared them to those induced by an acute LCMV infection.

Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy.

Chronic viral infections are characterized by a state of CD8 T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8 T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 T cells. Here we identify a population of virus-specific CD8 T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV).

Crucial roles of interleukin-7 in the development of T follicular helper cells and in the induction of humoral immunity.

Unlabelled: T follicular helper (Tfh) cells are specialized providers of cognate B cell help, which is important in promoting the induction of high-affinity antibody production in germinal centers (GCs). Interleukin-6 (IL-6) and IL-21 have been known to play important roles in Tfh cell differentiation. Here, we demonstrate that IL-7 plays a pivotal role in Tfh generation and GC formation in vivo, as treatment with anti-IL-7 neutralizing antibody markedly impaired the development of Tfh cells and IgG responses.

Safety and immunogenicity of therapeutic DNA vaccine with antiviral drug in chronic HBV patients and its immunogenicity in mice.

Background & Aims: Here, we evaluated the safety and immunogenicity of hepatitis B virus (HBV) DNA vaccine, HB-110, in mice and Korean patients with chronic hepatitis B (CHB) undergoing adefovir dipivoxil (ADV) treatment.

Methods: For animal study, mice (BALB/c or HBV transgenic) were immunized with mHB-110, and T-cell and antibody responses were evaluated. For clinical study, 27 patients randomly received either ADV alone or ADV in combination with HB-110.