The Mechanisms of CD8+ T Cells Exhaustion in the Tumor Microenvironment and Immune Therapy

In the tumor immune microenvironment, CD8+ T cells differentiate towards functional failure. The exhaustion of CD8+ T cells (Tex) showed varying degrees of effect dysfunction, loss of proliferation ability, and sustained high expression of a variety of inhibitory receptors, with metabolic and epigenetic changes. Tex cells are heterogeneous, including several subsets with different characteristics at different stages of differentiation. Immune checkpoint inhibitors (ICIs) can restore the effect or function of Tex cells, indicating that this T cell subset plays a key role in tumor immunotherapy. The understanding of the mechanism of CD8+ T cell exhaustion will be helpful to the implementation of tumor immunotherapy. This article reviews the production, differentiation and functional characteristics of Tex cells and their relationship with tumor immunotherapy.

Revolutionizing tumor immunotherapy:unleashing the power of progenitor exhausted T cells

In exploring persistent infections and malignancies, a distinctive subgroup of CD8^(+) T cells, progenitor exhausted CD8^(+) T(Tpex) cells, has been identified. These Tpex cells are notable for their remarkable self-renewal and rapid proliferation abilities. Recent strides in immunotherapy have demonstrated that Tpex cells expand and differentiate into responsive exhausted CD8^(+) T cells, thus underscoring their critical role in the immunotherapeutic retort. Clinical examinations have further clarified a robust positive correlation between the proportional abundance of Tpex cells and enhanced clinical prognosis. Tpex cells have found noteworthy applications in the formulation of inventive immunotherapeutic approaches against tumors. This review describes the functions of Tpex cells in the tumor milieu, particularly their potential utility in tumor immunotherapy. Precisely directing Tpex cells may be essential to achieving successful outcomes in immunotherapy against tumors.

Increased circulating level of interleukin-6 and CD8+T cell exhaustion are associated with progression of COVID-19

Background: Coronavirus disease 2019(COVID-19)is pandemic.It is critical to identify COVID-19 patients who are most likely to develop a severe disease.This study was designed to determine the clinical and epidemiological features of COVID-19 patients associated with the development of pneumonia and factors associated with disease progression.Methods:: Seventy consecutive patients with etiologically confirmed COVID-19 admitted to PLA General Hospital in Beijing,China from December 27,2019 to March 12,2020 were enrolled in this study and followed-up to March 16,2020.Differences in clinical and laboratory findings between COVID-19 patients with pneumonia and those without were determined by theχ2 test or the Fisher exact test(categorical variables)and independent group t test or Mann–Whitney U test(continuous variables).The Cox proportional hazard model and Generalized Estimating Equations were applied to evaluate factors that predicted the progression of COVID-19.Results: The mean incubation was 8.67(95%confidence interval,6.78–10.56)days.Mean duration from the first test severe acute respiratory syndrome coronavirus 2-positive to conversion was 11.38(9.86–12.90)days.Compared to pneumonia-free patients,pneumonia patients were 16.5 years older and had higher frequencies of having hypertension,fever,and cough and higher circulating levels of neutrophil proportion,interleukin-6,low count(<190/µl)of CD8+T cells,and neutrophil/lymphocyte ratio.Thirteen patients deteriorated during hospitalization.Cox regression analysis indicated that older age and higher serum levels of interleukin-6,C-reactive protein,procalcitonin,and lactate at admission significantly predicted the progression of COVID-19.During hospitalization,circulating counts of T lymphocytes,CD4+T cells,and CD8+T cells were lower,whereas neutrophil proportion,neutrophil/lymphocyte ratio,and the circulating levels of interleukin-6,C-reactive protein,and procalcitonin were higher,in pneumonia patients than in pneumonia-free patients.CD8+lymphocyte count in pneumonia patients did not recover when discharged.Conclusions: Older age and higher levels of C-reactive protein,procalcitionin,interleukin-6,and lactate might predict COVID-19 progression.T lymphocyte,especially CD8+cell-mediated immunity is critical in recovery of COVID-19.This study may help in predicting disease progression and designing immunotherapy for COVID-19.

Efficient control of chronic LCMV infection by a CD4 T cell epitope-based heterologous prime-boost vaccination in a murine model

CD4^(+)T cells are essential for sustaining CD8^(+)T cell responses during a chronic infection.The adoptive transfer of virus-specific CD4^(+)T cells has been shown to efficiently rescue exhausted CD8^(+)T cells.However,the question of whether endogenous virus-specific CD4^(+)T cell responses can be enhanced by certain vaccination strategies and subsequently reinvigorate exhausted CD8^(+)T cells remains unexplored.In this study,we developed a CD4^(+)T cell epitope-based heterologous prime-boost immunization strategy and examined the efficacy of this strategy using a mouse model of chronic lymphocytic choriomeningitis virus(LCMV)infection.We primed chronically LCMV-infected mice with a Listeria monocytogenes vector that expressed the LCMV glycoprotein-specific I-Ab-restricted CD4^(+)T cell epitope GP61–80(LM-GP61)and subsequently boosted the primed mice with an influenza virus A(PR8 strain)vector that expressed the same CD4^(+)T cell epitope(IAV-GP61).This heterologous prime-boost vaccination strategy elicited strong anti-viral CD4^(+)T cell responses,which further improved both the quantity and quality of the virusspecific CD8^(+)T cells and led to better control of the viral loads.The combination of this strategy and the blockade of the programmed cell death-1(PD-1)inhibitory pathway further enhanced the anti-viral CD8^(+)T cell responses and viral clearance.Thus,a heterologous prime-boost immunization that selectively induces virus-specific CD4^(+)T cell responses in conjunction with blockade of the inhibitory pathway may represent a promising therapeutic approach to treating patients with chronic viral infections.