ABSTRACT
Immunotherapy has completely changed the paradigm of clinical tumor treatment, but immune checkpoint inhibitors still have low objective response rates and are prone to drug resistance for most solid tumors. The immune suppression tumor microenvironment and complicated tumor immune escape mechanisms are key factors that affect the clinical outcome and response rates. Therefore, it is critical to reverse the obstacle of the tumor microenvironment to improve immunotherapy efficacy. The immune suppression caused by the increased level of adenosine in the tumor microenvironment raises the attention of people. Targeting adenosine receptors, especially A2AR, will be an effective strategy to improve immunotherapy efficacy. Targeting the adenosine-A2A pathway can increase immune infiltration, enhance immune cell function, and partially reverse immunotherapy-insensitive "cold tumors" to "hot tumors" to enhance treatment response rates and improve the efficacy of current immunotherapy. At present, many adenosine receptor inhibitors have shown good results in clinical trials, especially in combination with immune checkpoint inhibitors, chemotherapy, and adoptive cell transfer therapeutic drugs, which are expected to be used for tumor immunotherapy to bring new breakthroughs. This article reviews the accumulation mode of adenosine in the tumor microenvironment, the role of A2AR and their regulatory mechanism in immune response, the progress of A2AR inhibitors in clinical trials, potential risks to target A2AR, and the prospects for therapeutic targeting A2AR.
ABSTRACT
<p><b>OBJECTIVE</b>To analyze the association of transforming growth factor-beta1(TGF-beta1) gene +869T/C polymorphism and the serum level of TGF-beta1 in patients with early essential hypertension and early renal injury. To study the effect of the gene polymorphism of TGF-beta1 on the individual treatment with valsartan.</p><p><b>METHODS</b>Eighty patients with early essential hypertension and early renal injury were treated with valsartan, and their polymorphism of TGF-beta1 gene +869T/C was analyzed by sequence specific primers-polymerase chain reaction method. Before valsartan treatment and 8 weeks after the treatment, their urinary microamount albumin (MA) levels were determined by using radioimmunity method, and their serum levels of TGF-beta1 were determined by enzyme-linked immunosorbent assay.</p><p><b>RESULTS</b>The blood pressure level of patients with TGF-beta 1 gene +869 CC genotype, TT genotype, TC genotype showed no significant difference (P> 0.05) before treatment. The urinary MA level of the three genotypes was CC genotype's > TC genetype's > TT genotype's in sequence, and the urinary MA level of CC genotype was significantly higher than that of TC genotype and of TT genotype (P< 0.01). The serum levels of TGF-beta1 in the three genotypes was CC genotype's > TC genotype's > TT genotype's in sequence (P< 0.01). There was statistically significant positive correlation between the urinary MA level and the serum level of TGF-beta1(P< 0.05). After 8 weeks treatment with valsartan, there was significant decrease of the blood pressure, the urinary MA level, and the serum level of TGF-beta1. However, the blood pressure reduction of the three types had no statistical significant difference in sequence. The absolute value of urinary MA reduction was CC genotype's > TC genotype's > TT genotype's in sequence, the reduction absolute value of urinary MA in CC genotype was higher than that of TC genotype and of TT genotype (P< 0.05), but the reduction percentage of the urinary MA in the three genotypes showed no statistically significant difference (P> 0.05). The reduction of serum levels of TGF-beta1 was CC genotype's > TC genotype's > TT genotype's in sequence, there was significant difference between each other (P< 0.01). However, the reduction percentage of the serum level of TGF-beta 1 in the three types showed no statistically significant difference (P> 0.05).</p><p><b>CONCLUSION</b>(1) The renal injury of CC genotype in patients with early essential hypertension and early renal injury is more serious than that of TC genotype and of TT genotype. (2)The serum level of TGF-beta 1 can accurately indicate the severity of the renal injury and the protective effect on kidney with valsartan in patients with essential hypertension and early renal injury. (3)The treatment effect of valsartan in the patients with different TGF-beta 1 +869T/C genotype has no difference, i.e., besides effectively decreasing the blood pressure and protecting the renal function, valsartan can reduce the serum level of TGF-beta1 without the influence of the gene polymorphism of TGF-beta1.</p>