Advances in application of regulatory T cells in transplant immune tolerance: from basic to clinical research / 器官移植

Regulatory T cells (Treg) are important inhibitory immune cells to establish immune tolerance, which play a pivotal role in regulating excessive immune response and autoimmune diseases of the host. Previous studies related to transplant immune tolerance have confirmed that increasing the number of Treg in vivo or enhancing the function of Treg serve as a therapeutic strategy to induce transplant immune tolerance. At present, Treg-based induction methods for transplant immune tolerance include adoptive infusion of Treg, in vivo amplification of Treg and utilization of antigen-specific Treg. In this article, the characteristics and mechanism of Treg, the latest research progress on basic experiments and clinical practice of Treg related to transplant immune tolerance at home and abroad were reviewed, and future challenges and development of Treg therapy were prospected, aiming to unravel the significance and application prospect of Treg in transplant immune tolerance, explore the advantages and limitations of Treg therapeutic strategies, and provide reference and evidence for subsequent research in this field.

Quality evaluation of anti-PD-1/CTLA-4 bispecific antibody / 中国生物制品学杂志

@#Objective Establish quality control methods for critical quality attribute of bispecific antibody against programmed cell death protein 1(PD-1)/cytotoxic T-lymphocyte-associated protein 4(CTLA-4).Methods The biological activity of PD-1 target was determined by reporter gene assay,and the competitive binding activity of CTLA-4 target was determined by flow cytometry;The antibody molecular size variants were controlled by reducing/non-reducing capillary electrophoresis-sodium dodecyl sulfonate(CE-SDS) and size exclusion chromatography-high performance liquid chromatography(SEC-HPLC);Charge heterogeneity was determined by imaging capillary isoelectric focusing electrophoresis(iCIEF);Bispecific anti-PD-1/CTLA-4 antibody was identified by peptide map analysis;Glycosylation was analysed by high performance liquid chromatography(HPLC)Results The concentration for 50% of maximal effect(EC_(50)) of PD-1target was(6.91±0.78) nmol/L,and the relative biological potency to the reference was(103.50±13.08)% with the RSD of 12.64%;The EC_(50) of CTLA-4 target activity was(0.35±0.28) nmol/L,and the relative biological potency was(99.30±9.15)% with the RSD of 8.32%.The percentage of peak area of light chain and heavy chain of reducing CE-SDS was(98.86±0.02)%.The main peak area percentage of non-reducing CE-SDS was(93.07±0.13)%,fragment percentage was(4.44±0.13)%,and polymer percentage was(2.49±0.15)%.The peak area percentage of SEC-HPLC monomer and polymer were(97.20±0.01)% and(2.68±0.01)%,respectively.The area percentage of peak A group,peak B group,peak C group and peak D group were(38.43±0.54)%,(43.26±0.32)%,(11.31±0.14)% and(7.00±0.17)%,respectively.Peptide mapping showed the specific spectrum of the bispecific anti-PD-1/CTLA-4 antibody,which could be adopted for identification test.The highest proportion of glycotype was GOF,with a content of(41.06±0.11)%,There were three types of glycan containing sialic acid,namely G2F+G1F-NANA,G2F-NANA and G2F-2NANA,with the content of(12.44±0.12)%,(12.00±0.05)% and(5.37±0.05)%,respectively.The total content of glycan containing sialic acid was(29.80±0.20)%.Conclusion The critical quality attributes of bispecific anti-PD-1/CTLA-4 antibody were studied and the corresponding quality control methods were established to ensure its safety,effectiveness and quality control,which provides a reference for the quality control methods and strategies of this type of monoclonal antibody products.

Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms and strategies / 医学前沿

Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

Liver-directed treatment is associated with improved survival and increased response to immune checkpoint blockade in metastatic uveal melanoma: results from a retrospective multicenter trial / 医学前沿

Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.

Association of Toll-like receptor 7, CTLA-4 gene polymorphisms with severe asthma / 公共卫生与预防医学

Objective To explore the association of Toll-like receptor 7, CTLA-4 gene polymorphisms and severe asthma. Methods From February 2018 to March 2020, 175 asthma patients admitted to the respiratory department of our hospital were selected as the research subjects (109 cases of mild disease and 66 cases of severe disease), and 248 cases of healthy people who were included in the outpatient physical examination of our hospital during the same period were selected as the normal control group. Toll-like receptor 7 and CTLA-4 gene polymorphisms in the above groups were determined, and the relationship between Toll-like receptor 7 and CTLA-4 polymorphisms and severe asthma was evaluated by calculating the odds ratio (OR) and 95% confidence interval(CI). The relationship between the genotypes of Toll-like receptor 7 and CTLA-4 polymorphisms and severe asthma were evaluated by logistic regression analysis. Results The proportion of TLR7 rs3853839 CC genotype, CTLA-4 rs231725 AA genotype, TLR7 rs3853839 C allele frequency and CTLA-4 rs231725 A allele frequency in severe asthma group and mild asthma group were higher than those in normal control group(P<0.05). The proportion of TLR7 rs3853839 CC genotype, the proportion of CTLA-4 rs231725 AA genotype, the frequency of TLR7 rs3853839 C allele, and the frequency of CTLA-4 rs231725 A allele in the severe asthma group were higher than those in the mild asthma group(P<0.05). TLR7 rs3853839 CC genotype (OR=10.32, 95%CI=5.59-23.89), CTLA-4 rs231725 AA genotype (OR=13.21, 95%CI=3.58-20.25), TLR7 rs3853839 C allele frequency (OR=11.32, 95% CI=4.25-21.14) and CTLA-4 rs231725 A allele frequency (OR=13.24, 95% CI=6.59-20.21) could increase the susceptibility to severe asthma(P<0.05). TLR7 rs3853839CC genotype, TLR7 rs3853839C allele frequency, CTLA-4 rs231725AA genotype and CTLA-4 rs231725A allele frequency were risk factors for severe asthma(P<0.05). Conclusion TLR7 rs3853839 CC genotype, TLR7 rs3853839 C allele frequency, CTLA-4 rs231725 AA genotype and CTLA-4 rs231725 A allele frequency are associated with the occurrence of severe asthma.

Correlation Between PD-1/CTLA-4 Expressions with C linicopathological Features and Prognosis of Osteosarcoma Patients / 肿瘤防治研究

Objective To explore the expression of PD-1 and CTLA-4 in osteosarcoma and their clinical significance. Methods Fifty-eight cases of osteosarcoma encountered from 2007 to 2016 were enrolled. The expression levels of PD-1 and CTLA-4 were detected through immunohistochemistry (EnVision method). Results PD-1 was positively expressed in 31 (53.4%) cases and negatively expressed in 27 (46.6%) cases. CTLA-4 was positively expressed in 19 (32.8%) cases and negatively expressed in 39 (67.2%) cases. A total of 12 (20.7%) cases were PD-1 and CTLA-4 double positive, whereas 20 (34.5%) cases were double negative, and 26 (44.8%) cases were single positive. The positive expression of PD-1 was correlated with neoadjuvant chemotherapy, tumor metastasis and relapse, and shortened survival time (P < 0.05). The positive expression of CTLA-4 was partly related with late Ennecking stage (P=0.051). Double positive expression was related to the highest tumor metastasis and relapse rates and the worst prognosis (P < 0.05), compared with double negative and single positive expression. Conclusion Positive expression of PD-1 and CTLA-4 in osteosarcoma is associated with worse prognosis, whereas double positive expression is associated with the highest tumor relapse and metastasis rates and shortest survival time. These results are potential valuable references for osteosarcoma immunotherapy.

Bioinformatics-based design of a fusion vaccine with CTLA-4 variable region to combat Brucella

Brucellosis has become a global zoonotic disease, seriously endangering the health of people all over the world. Vaccination is an effective strategy for protection against Brucella infection in livestock in developed countries. However, current vaccines are pathogenic to humans and pregnant animals, which limits their use. Therefore, it is very important to improve the safety and immune protection of Brucella vaccine. In this study, different bioinformatics approaches were carried out to predict the physicochemical properties, T/B epitope, and tertiary structure of Omp2b and Omp31. Then, these two proteins were sequentially linked, and the Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) variable region was fused to the N-terminal of the epitope sequence. In addition, molecular docking was performed to show that the structure of the fusion protein vaccine had strong affinity with B7 (B7-1, B7-2). This study showed that the designed vaccine containing CTLA-4 had high potency against Brucella, which could provide a reference for the future development of efficient brucellosis vaccines.

Expression of cytotoxic T lymphocyte-associated antigen 4, CD44, and E-cadherin in the microenvironment of breast carcinomas

SUMMARY OBJECTIVE: The expression of cytotoxic T lymphocyte-associated antigen 4, E-cadherin, and CD44 in the area of tumor budding was investigated in breast carcinomas in our study. METHODS: Tumor budding was counted at the invasive margins in 179 breast carcinomas. To understand the microenvironment of tumor budding, we examined the expression status of the immune checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4, E-cadherin, and CD44. RESULTS: Tumors were separated into low (≤5) and high tumor budding groups (>5) based on the median budding number. Lymphovascular, perineural invasion, and the number of metastatic lymph nodes were significantly higher in high-grade budding tumors (p=0.001, p<0.001, and p=0.019, respectively). Tumor-infiltrating lymphocytes were significantly higher in tumors without tumor buddings (p<0.001). When the number of budding increases by one unit, overall survival decreases by 1.07 times (p=0.013). Also, it increases the risk of progression by 1.06 times (p=0.048). In high tumor budding groups, the cytotoxic T lymphocyte-associated antigen 4 staining percentage of lymphocytes was significantly higher (p=0.026). With each increase in the number of buds, an increase in the percentage of cytotoxic T lymphocyte-associated antigen 4 staining was seen in lymphocytes in the microenvironment of TB (p=0.034). CONCLUSION: Tumor budding could predict poor prognosis in breast carcinomas, and anti-cytotoxic T lymphocyte-associated antigen 4 immunotherapies may be beneficial in patients with high tumor budding tumors.

Role of CTLA4 immunohistochemistry in the diagnosis of colon cancers

Background: There are a wide range of diagnostic markers for colorectal cancers like detection of mutated KRAS, TP53, and APC genes. However, genetic and immunological factors have also been attributed to the cancer prognosis. The present study was carried out to evaluate the expression of CTLA-4 in colorectal cancers. Methods: This cross-sectional study was carried out among 30 resected specimens of colorectal cancer. Paraffin blocks were made on samples from tumor areas along with adjacent normal areas. Immunohistochemistry for CTLA-4 was done on the sections along with controls. Gross findings were recorded from the blocks. Blocks with section containing normal epithelium and tumor were chosen for immunohistochemistry. Results: Overexpression of CTLA-4 was observed in 43.3% of the tumors. There was a significantly high tumor infiltration among those specimens showing overexpression of CTLA-4. The observed difference was statistically significant (P < 0.05). On comparing the grade of the tumor with intensity of CTLA4 uptake, it was observed that majority of the well-differentiated tumors (66.7%) had an intensity of 1+ whereas majority of the poorly differentiated tumors had an intensity of 3+ (66.7%). Conclusion: The present study has demonstrated overexpression of CTLA-4 in colorectal cancer specimens, and also highlighted the potential scope for anti-CTLA-4 agents like Ipilimumab in cancer therapy. The need for further evaluation to examine five-year survival with such immunotherapies is essential to document candid therapeutic recommendations for colorectal cancers.

Association between the CTLA4 +49A/G (rs231775) and CT60 (rs3087243) gene variants with vitiligo: study on a Mexican population

Abstract Background: Vitiligo is characterized by an autoimmune response targeting melanocytes, thus resulting in skin depigmentation. There are several genetic components involved in the development of vitiligo, of which various gene polymorphisms are currently considered as risk factors. For example, the CTLA4 (T-lymphocyte antigen 4) +49A/G (rs231775) and CT60 (rs3087243) gene variants have been associated with a predisposition for autoimmune diseases in different populations; however, their involvement in the development of vitiligo remains controversial. Objective: We evaluated the association between vitiligo and the CTLA4 +49A/G (rs231775) and CT60 (rs3087243) gene variants in a Mexican population. Methods: A total of 116 vitiligo patients and 117 control subjects from northeast Mexico were included in the study and analyzed through PCR-RFLP to determine whether there is an association between vitiligo and CTLA4 +49A/G (rs231775) and CT60 (rs3087243) gene variants. Results: No statistical difference was observed for both gene polymorphisms between vitiligo patients and controls (p > 0.05). Otherwise, vitiligo activity, family history of vitiligo, personal history of autoimmune diseases, or sex did not show any difference (p > 0.05). Conclusion: As suggested by the analysis of a northeastern Mexican population, the CTLA4 +49A/G (rs231775) and CT60 (rs3087243) gene variants do not constitute a risk factor in the development of vitiligo.

La inhibición de los puntos de control inmunológico, una terapia en evolución: remembranza del Premio Nobel de Medicina 2018 / Immune checkpoint inhibitors: a breakthrough in cancer therapy

Professors James P. Allison and Tasuku Honjo were awarded with the 2018 Nobel Prize in Medicine for their contributions in cancer immunotherapy. The latter is a breakthrough in cancer therapy, aimed to overcome tumor-induced immunosuppression, leading to the reactivation of the immune system against cancer cells. Under physiological conditions, the CTLA-4 and PD-1 proteins expressed on T-cells and discovered by the awarded scientists, lead to immune tolerance. Cancer cells exploit these control points to enhance the inhibition of T-cells. The expression of PD ligands (PD-L1) in tumor cells and CTLA-4 ligands in antigen presenting cells, which bind the PD-1 receptor and CTLA-4 respectively, block anti-tumor immunity. This situation led to a biotechnological race focused on the development of effective antibodies able to "turn-on" the immune system cheated by the tumor. Anti-CTLA-4 and anti-PD-1 antibodies improve life-expectancy in cancer patients. In this review, we perform an historical overview of Professors Allison and Honjo contribution, as well as the immunological basis of this new and powerful therapeutic strategy, highlighting the clinical benefits of such intervention.

Cutaneous immune-related adverse reactions induced by immune checkpoint inhibitors / 中华皮肤科杂志

As a new type of anti-cancer drugs, immune checkpoint inhibitors have been widely used for the treatment of various tumors in recent years, but they have also caused a variety of immune-related adverse reactions, among which cutaneous adverse reactions are the most common. The onset of cutaneous adverse reactions is usually early, and most are mild, but some can also be life-threatening. This review summarizes recent advances in cutaneous immune-related adverse reactions induced by immune checkpoint inhibitors.

Immune Checkpoint Molecules in Cancer Cells: Not in Their Places but on Their Duty / 中国生物化学与分子生物学报

Immune checkpoints represent a group of inhibitory receptor molecules that are expresses in the surface of immune cells and play a pivotal role in maintaining immune homeostasis. In recent years, several key immune checkpoint molecules such as CTLA-4 and PD-1, has been found to exist in some kinds of tumor cells. These ectopic expressed checkpoint molecules are named as “cancer cell-intrinsic immune checkpoint molecules”. Although our understanding on cancer cell-intrinsic immune checkpoint molecules is quite limited, emerging evidence suggests that the expression and the biological functions of such molecules in different types of cancer cells are heterozygous and diverse. In particular, the discovery of “adaptive immune-independent” regulation on cancer cell behaviors would potentially benefit to design a customized cancer immune therapy, as well as to develop new therapeutic strategies for cancer. In this review, we will briefly describe the timeline of the studies, deeply discuss the complicated biological functions and the regulatory mechanisms (CTLA-4 and PD-1 as representative examples). And finally we put forward a research perspective on cancer cell-intrinsic immune checkpoint molecules. This review aims to present and promote the studies of cancer cell-intrinsic immune checkpoint molecules to the broad scientific community.

Biomarkers for evaluating the prognosis of non-small cell lung cancer treated with immune checkpoint inhibitors / 中国肿瘤生物治疗杂志

@#[摘 要] 免疫检查点抑制剂（ICI）是一种备受关注的肿瘤免疫治疗手段，可通过阻断免疫检查点信号转导来恢复甚至增强T淋巴细胞的抗肿瘤免疫反应以达到抗肿瘤的治疗目的。PD-L1表达水平或可作为派姆单抗的一线使用标准；较高的肿瘤突变负荷（TMB）增加癌细胞抗原表达，使后者易被免疫细胞监视定位并清除，被定义为预测ICI疗效的生物标志物；错配修复基因（MMR）与MSI具有高度一致性，在多种实体瘤中具有预后预测作用；肿瘤浸润淋巴细胞联合TNM分期评估非小细胞肺癌患者预后准确性甚至优于病理标准，通过检测炎症因子的基因表达水平评估T细胞炎症基因表达谱可预测ICI的治疗效果；体细胞突变状态与免疫治疗的预后有关；低水平的中性/淋巴细胞比值（NLR）可能是免疫相关不良事件发生的独立预测因素；肠道微生物通过影响TIL水平干预免疫治疗的效果；除此以外还有其他预测因素可供参考。梳理总结预测相关标志物，分析其价值性与局限性，可为临床选择适合患者的治疗方案，也可使患者临床获益达到最大。

Efficacy and safety of nivolumab plus ipilimumab versus nivolumab monotherapy in the treatment of malignant tumors: A Meta-analysis / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To systematically evaluate the efficacy and safety of nivolumab plus ipilimumab versus nivolumab monotherapy in the treatment of malignant tumors, so as to provide evidence-based medical proof for clinical administration. Methods: Databases, such as PubMed, CNKI, VIP, and Wanfang Data, were searched from January 2000 to January 2022 to collect the clinical trial data in terms of nivolumab plus ipilimumab versus nivolumab monotherapy for malignant tumors were published in both domestic and abroad. Two reviewers independently evaluated the quality of included RCTs, and extracted and cross-checked the data. RevMan 5. 4 was used for the Meta-analysis. Results: A total of 7 RCTs studies including 10 articles were included. Compared with the nivolumab monotherapy group, the OS of patients in the combined treatment group was significantly improved (HR=0.86, 95% CI:0. 75-0.99, P=0. 03), and the PFS was significantly prolonged (HR=0.69, 95% CI: 0.55-0.85, P=0.000 6). However, as for safety, treatment-related adverse events (OR=3.18, 95% CI: 1.55-6.55, P=0.002) and adverse events leading to drug discontinuation (OR=7.11, 95% CI: 4.85-10.42, P<0.000 01) in the combination therapy group were significantly higher than those in the monotherapy group. Conclusion: Compared with nivolumab monotherapy, nivolumab plus ipilimumab can significantly improve the OS and PFS of tumor patients, but is also associated with more treatment-related adverse events and adverse events leading to drug discontinuation. Therefore, it is necessary to pay attention to follow-up and regular monitoring to prevent the occurrence of serious adverse reactions.

Dual Immunotherapy in Advanced Non-small Cell Lung Cancer: the Progress and Clinical Application / 中国肺癌杂志

Programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors and PD-1 inhibitors plus chemotherapy combination regimens have been widely used in the first-line treatment of advanced non-small cell lung cancer(NSCLC), but patients with low PD-L1 expression have limited objective response and survival benefits. Existing treatment regimens are still difficult to fully meet the clinical needs of patients in the real world. Therefore, researchers are still exploring novel superactive treatment options to further improve the efficacy and survival prognosis of different sub-groups in NSCLC. Dual immunotherapy [such as the combination of PD-1 and cytotoxic T lymphocyte associated antigen-4 (CTLA-4) inhibitors] has shown considerable long-term survival benefits in a variety of tumors and has also shown broad clinical prospects in NSCLC. In addition to exploring different emerging combination options, how to accurately identify the optimal-benefit groups through predictive biomarkers and how to effectively manage the safety of combination immunotherapy through multidisciplinary collaboration are also the focus of dual immunotherapy. This article reviews the mechanism of action, research progress, predictive biomarkers and future exploration directions of dual immunotherapy.
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The functions of co-signaling molecules and their clinical applications in cancer therapy / 中国肿瘤生物治疗杂志

@#[摘 要] B7/CD28家族分子作为主要的共信号分子，在T细胞功能调控及免疫应答中发挥着至关重要的作用，关于其功能的研究及应用在世界范围内广泛开展。其中，CD28和CTLA-4都可以与B7-1/B7-2结合，但CD28能够促进T细胞增殖，维持Treg细胞稳态；而CTLA-4则可以抑制T细胞增殖，影响CD4+T细胞的分化；抗CTLA-4单抗ipilimumab与抗PD-1单抗联用能够用于治疗PD-L1+的非小细胞肺癌以及无症状的Ⅳ期黑色素瘤。PD-L1/PD-L2：PD-1途径则可以通过多种方式调节T细胞功能，参与CD8+T细胞“耗竭”状态的形成与维持。目前，针对PD-L1/PD-L2：PD-1途径的免疫治疗相关药物开发广泛且较为成熟，抗PD-1单抗主要通过诱导肿瘤浸润的部分耗竭的CD8+T细胞亚群的扩增发挥抗肿瘤作用。ICOS：ICOSL途径在T细胞分化、细胞因子分泌以及体液免疫应答中起着重要作用，抗ICOS抗体药物feladilimab与抗PD-1单抗联用能够有效治疗多发性或难治性骨髓瘤。B7-H3同时具有共刺激效应和共抑制效应，阻断B7-H3后能够有效增强TIL的抗肿瘤效应，其单抗enoblituzumab能够与抗PD-1单抗联用治疗非小细胞肺癌。B7-H4、人内源性逆转录病毒‑H长末端重复关联蛋白（human endogenous retrovirus‑H long terminal repeat‑associating protein，HHLA）以及含V结构域抑制T细胞活化的免疫球蛋白（V‑domain Ig‑cotaining suppressor of T cell activation，VISTA）均能够提供抑制信号，针对B7-H4靶点的CAR-T治疗以及VISTA的小分子抑制剂CA-170均有临床试验正在进行中。目前，对共信号分子的研究已经获得了长足进展，针对某些活化性分子或者抑制性分子开发了相关抗肿瘤药物并在临床中取得一定成效，但如何进一步提高其治疗有效率、减少不良反应等仍有待探索。

Research progress on combined treatment of radiotherapy and anti-CTLA-4 antibody / 中华放射肿瘤学杂志

Radiotherapy (RT) is one of the three prevailing therapeutics for tumors. With rapid development of immunotherapy (IM), the combination of IM and RT has gainned increasingly widespread attention. Cytotoxic T lymphocyte associated protein-4(CTLA-4) inhibitor is an important checkpoint target in immune activation and regulation, which exerts significant anti-tumor effects in melanoma and non-small cell lung cancer, etc. Accordingly, the combination of RT and anti-CTLA-4 antibody has become a hot spot. This article reviews research progress on pre-clinical and clinical evidences of RT combined with anti-CTLA-4 antibody, which provides evidence for further exploration in this field.

CTLA-4 +49 A/G Polymorphism and the Risk of Lung Cancer: a Meta-analysis / 中国肺癌杂志

BACKGROUND@#Lung cancer is one of the malignant tumors. Gene mutations associated with cellular immune function and regulating the activation and proliferation of immune cells. Several publications have explored the relationship between cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 adenine (A)/guanine (G) polymorphism and susceptibility of lung cancer, but the results remain controversial. Thus, we performed this meta-analysis to derive a more comprehensive estimation of the relationship.@*METHODS@#All articles addressed lung cancer and polymorphisms of CTLA-4 were searched from the PubMed, EMBASE databases published up to June 29, 2019. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Publication bias of relevant studies was examined via Begg's test and funnel plots.@*RESULTS@#The meta-analysis included 8 case-control studies covering 4,430 lung cancer patients and 5,198 healthy controls from September 2008 to April 2020. The overall eligible data indicated that CTLA-4 +49A/G polymorphisms did not correlate with the elevated lung cancer risk in all genetic comparison models (dominant model: OR=1.037, 95%CI: 0.925-1.161; recessive model: OR=0.968, 95%CI: 0.888-1.055; allele model: OR=0.992, 95%CI: 0.933-1.054; homozygous model: OR=0.980, 95%CI: 0.857-1.121; heterozygous model: OR=1.023, 95%CI: 0.906-1.154). In further stratified analyses, CTLA-4 +49A/G polymorphism was found to be significantly associated with susceptibility to NSCLC in these models (dominant model: OR=1.404, 95%CI: 1.074-1.836; allele model: OR=1.273, 95%CI: 1.034-1.565; homozygous model: OR=1.553, 95%CI: 1.044-2.310; heterozygous model: OR=1.308, 95%CI: 1.062-1.611).@*CONCLUSIONS@#CTLA-4 +49A/G polymorphism were not associated with the risk of lung cancer but might be a risk factor only in NSCLC.

Advance of synergism of immune checkpoint blockade and anti-angiogenesis in cancer treatment / 中国药理学通报

Immune checkpoint inhibitor ( ICI) activates the host' s anti-tumor immune response by blocking negative regulatory immune signals. A series of clinical trials showed that ICI could effectively induce tumor regression in a subset of advanced cancer patients. Anti-angiogenesis drugs commonly used to block tumor angiogenesis can inhibit the growth of tumors, but they cannot improve the survival of patients with limitations in application such as drug resistance. Tumor immune response is closely related to angiogenesis. In turn, tumor angiogenesis highly depends on immunosuppressive microenvironment. Recent studies have indicated that ICI resistance could be alleviated by combination therapy with anti-angiogenesis treatment, and the efficacy of combination therapy was superior to that of monotherapy. The reciprocal regulation between tumor vascular normalization and immune reprogramming forms a reinforcing loop that reconditions the tumor immune microenvironment to induce durable antitumor immunity. This review clarifies the latest understanding of ICI combined anti-angiogenesis therapy and provides ideas for subsequent research.