PD1 PDL1在癌症发生发展和预后的关系

PD-1/PD-L1与癌症的发生发展、转移及用药和预后的关系PD-1/PD-L1信号通路在免疫调控上，尤其在T细胞功能耗竭中发挥重要作用，由于PD-L1表达的广泛性，PD-1/PD-L1信号通路与自身免疫性疾病、恶性肿瘤、病毒感染性疾病等在内的多种疾病密切相关。

1、PD-1：可表达于活化的CD4+ T细胞，CD8+ T细胞，Treg细胞、B细胞、NK 细胞、单核细胞和DCs。

在肿瘤发生的状态下，PD-1在T细胞上呈现高表达，PD-1表达水平随疾病的进展而增加[1]。

在胃癌患者中表达及其临床意义的荟萃分析结果显示，PD-1 表达与淋巴结转移、淋巴管浸润有关；
PD-1 与PD-L1 的表达与胃癌患者预后的关系仍存争议。

一般认为PD-1 高表达提示癌症患者的无病生存期（disease-free survival，DFS）较短。

对465 例胃癌患者的临床观察研究发现，PD-1 表达结果与病理以及预后均无相关性[4]。

2、PD-L1可表达于多种细胞，包括单核-巨噬细胞、T细胞、B细胞、DCs和肥大细胞等免疫细胞，以及内皮细胞，胎盘、胰岛细胞及大多数肿瘤细胞等非炎性细胞。

PD-L1则通常在肿瘤浸润淋巴细胞及恶性肿瘤细胞上表达，通过诱导抑制信号来阻断肿瘤特异性T细胞的增值，从而导致抗肿瘤免疫功能失常[2]。

相对而言，PD-L1在肿瘤细胞上的表达较其在免疫细胞中的表达水平更高。

PD-L1在不同类型肿瘤中的表达水平明显不同，在肺癌、黑素和肾细胞癌中高表达，而在结肠癌和前列腺癌中呈现较低的表达水平。

在预后方面，在非小细胞肺癌、胃食管癌、黑素瘤和肾细胞癌中和TILs上高表达PD-L1与不良预后相关；在乳腺癌和晚期浆液性卵巢癌中，PD-L1表达则表示良好的预后[3]。

PD-L1 在胃肿瘤、基质和免疫细胞表面均呈阳性，其表达水平与浸润深度、淋巴结转移、远处转移、血管浸润和恶性程度显著相关。

PD-L1 表达情况（表达位置）因肿瘤类型而异，如EBVa GC 型肿瘤细胞
中PD-L1 表达多见于大血管附近，MSI 型胃癌则见于肿瘤与非肿瘤组织交界处。

与其他类型胃癌相比，EBVa GC 型胃癌患者PD-L1 阳性率更高，在肿瘤细胞和肿瘤浸润免疫细胞中均可观察到PD-L1 高表达的趋势。

PD-1/PD-L1信号通路在免疫调控上，尤其在T细胞功能耗竭中发挥重要作用，由于PD-L1表达的广泛性，PD-1/PD-L1信号通路与自身免疫性疾病、恶性肿瘤、病毒感染性疾病等在内的多种疾病密切相关。

一项包含105例胃癌患者的研究结果显示，肿瘤细胞表达的PD-L1 与不良预后相关，肿瘤细胞PD-L1 阳性者OS 为14.2 个月，而PD-L1 阴性者则为18.6 个月，二者差异具有统计学意义（P ＝0.025）[5]。

参考文献：
[1] Balar A V, Weber J S. PD-1 and PD-L1 antibodies in cancer: current status and future directions[J]. Cancer Immunology, Immunotherapy, 2017, 66(5): 551-564.
[2] Salmaninejad A, Khoramshahi V, Azani A, et al. PD-1 and cancer: molecular mechanisms and polymorphisms[J]. Immunogenetics, 2018, 70(2): 73-86.
[3] 李皓月, 李金霞, 申力. PD-1/PD-L1 与胃癌的关系及临床应用[J]. 肿瘤, 2019 (10): 10.
[4] Böger C, Behrens H M, Mathiak M, et al. PD-L1 is an independent prognostic predictor in gastric cancer of Western patients[J]. Oncotarget, 2016, 7(17): 24269.
[5] Ju X, Shen R, Huang P, et al. Predictive relevance of PD-L1 expression with pre-existing TILs in gastric cancer[J]. Oncotarget, 2017, 8(59): 99372.
3、胃癌：根据Lauren 分型，胃癌可分为肠型、弥漫型和混合型，PD-1 阳性患者多为肠型。

(1)In the present study, we analyzed the percentages of T-helper (Th)-17/regulatory T (Treg) cells and PD-1/PD-L1 expression on peripheral blood mononuclear cells (PBMCs) during the perioperative period. In patients who underwent gastric cancer resection, the number of Th17 c6ells decreased, whereas the number of Treg cells increased, accompanied by an increased expression of PD-1/PD-L1. In addition, the expression of RORgammat and IL-17 decreased, whereas the expression of Foxp3 and TGF-beta1 increased. Our study demonstrated that gastric cancer resection altered the balance of Th17/Treg cells and increased PD-1/PD-L1 expression
胃癌切除前后CD4+ PD-1+ T细胞占PBMC的比例：6.34%-21.1%；PD-L1+ T细胞占PBMC的比例：5.94%-20.4%。

[6] Zheng X, Dong L, Wang K, et al. MiR-21 participates in the PD-1/PD-L1 pathway-mediated imbalance of Th17/Treg cells in patients after gastric cancer resection[J]. Annals of surgical oncology, 2019, 26(3): 884-893. (IF:3.681)
（2）The frequency of CD4(+)PD-1(+) and CD8(+)PD-1(+) cells in GC patients was higher than in the control group (p < 0.0001 and p < 0.01, respectively). Expression of PD-1 on CD8(+) cells in GC was higher than in the control group (p < 0.0001). The frequency of CD4(+)PD-L1(+) and CD8(+) PD-L1(+) cells was higher than in the control group (p < 0.0001). Expression of PD-L1 on CD4(+) and CD8(+) cells in GC was higher than in the control group (p < 0.0001). Downregulation of peripheral blood CD4(+) and CD8(+) lymphocytes can be associated with PD-1/PD-L1
expression. This can lead to attenuation of the general immune response in GC.
CD4+PD-1+细胞占比21.91%，CD4+PD-L1+细胞占比22.01%；CD8+PD-1+细胞占比15.52%，CD8+PD-1+细胞占比12.16%。

与对照组相比上调。

[7] Zgodzinski W, Grywalska E, Zinkiewicz K, et al. Peripheral blood T lymphocytes are downregulated by the PD-1/PD-L1 axis in advanced gastric cancer[J]. Archives of medical science: AMS, 2019, 15(3): 774. （IF:2.38)。

（3）Among 55 valid PD-L1 IHC staining results from the monotherapy cohort, 14.5% were PD-L1 positive and 85.5% were PD-L1 negative. PD-L1 positive patients responded significantly better than PD-L1 negative patients (ORR 37.5% versus 8.5%, P = 0.023; Figure 1C). PD-L1 positive patients also had high value in median PFS (5.5 versus 1.9 months, P= 0.092) and median OS (12.1 versus 5.3 months, P= 0.45),
although the survival differences were not statistically significant
PD-L1在组织中表达高，预后良好。

[8] Wang F, Wei X L, Wang F H, et al. Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD1 antibody in phase Ib/II clinical trial NCT02915432[J]. Annals of Oncology, 2019. (IF:14.196)
（4）Five-year overall survival rates differed significantly between the groups with low and high frequency of PD1(+)CD4(+) T-cells (75.1% vs. 27.2%, respectively; p=0.0008). The 5-year overall survival rates were 78.3% and 37.2%, respectively, for the corresponding PD1(+)CD8(+) T-cell subgroups (p=0.0004)。

（胃癌中低PD-1CD4+T cell，五年生产率高，高PD-1CD4+T cell，五年生产率低）。

[9] PD-1 Expression on Circulating CD8+ T-Cells as a Prognostic Marker for Patients With Gastric Cancer.(IF:1.9)
（5）PD-1 expression on CD4+ and CD8+ T cells from gastric cancer patients was significantly higher than that from normal controls. PD-1 expression on CD4+ and
CD8+ T cells was related to disease progression. Furthermore, PD-1 expression on CD4+ and CD8+ T cells from gastric cancer tissue was significantly higher than that from normal gastric mucosa and PBMC. PD-1 positive CD4+ and CD8+ T cells produced significantly less IFN-gamma than PD-1 negative CD4+ and CD8+ T cells. CONCLUSIONS: Upregulation of PD-1 on both CD4+ and CD8+ T cells may be, in part, responsible for immune evasion in gastric cancer patients.(PBMC)
[10] Saito H, Kuroda H, Matsunaga T, et al. Increased PD‐1 expression on CD4+ and CD8+ T cells is involved in immune evasion in gastric cancer[J]. Journal of surgical oncology, 2013, 107(5): 517-522. (IF:3.114).
(6)B7-H1 and PD-1 expressions are increased in gastric carcinoma. This signaling pathway may inhibit antitumor immune responses in gastric carcinoma. B7-H1 expression plays a critical role in the pathogenesis of human gastric carcinoma,and might be a promising prognostic marker and therapeutic target in the treatment of this disease.
[11] Liu S M, Meng Q, Zhang Q X, et al. Expression and significance of B7-H1 and its receptor PD-1 in human gastric carcinoma[J]. Zhonghua zhong liu za zhi [Chinese journal of oncology], 2008, 30(3): 192-195.(IF: 3.411)
(7)High serum PD-L1 level was a prognostic factor for reduced overall survival in patients with surgically treated gastric cance
[12] Masaaki I , Yoko O , Satoshi Y , et al. Is high serum programmed death ligand 1 level
a risk factor for poor survival in patients with gastric cancer?[J]. Annals of Gastroenterological Surgery, 2018, 2(4):313-318.
肺癌：
（1）High PD-L1 expression was also correlated with poor prognosis in terms of the OS of patients with NSCLC (pooled HR = 1.75, 95% CI: 140-2.20, p < 0.001; heterogeneity test: I(2) = 0%, p = 0.643). CONCLUSIONS: NSCLC patients with positive PD-L1 expression exhibited poor OS. The PD-L1 expression was higher in tumors with poor differentiation.
[13] Wang A, Wang H Y, Liu Y, et al. The prognostic value of PD-L1 expression for non-small cell lung cancer patients: a meta-analysis[J]. European Journal of Surgical Oncology (EJSO), 2015, 41(4): 450-456.
（2）38例肺腺癌(A组)、35例肺鳞癌(B组)患者作为实验组，以30例健康体检者(C组)作为对照组，A、B、C组外周血中PD-1表达水平分别为(104.98±20.76)、(109.13±24.65) 和(50.80±14.38) pg/ml，实验组高于对照组，差异有统计学意义（ELISA法检测）。

NSCLC组、健康对照组PD-1+CD8+T表达率分别为(16.73±3.93)%和(7.92±2.00)%，差异有统计学意义(t=11.764,P＜0.05)（流式检测外周血）。

[14] 周莉. PD-1在非小细胞肺癌表达及预后中的应用研究[D].
乳腺癌：
（1）乳腺癌组PD-1 在外周血CD4+T、CD8+T 细胞表面上的表达率明显高于健康组，且差异显著，有统计学意义（P＜0.05）。

在肿瘤分期、淋巴结转移情况、远处转移情况、肿瘤分化程度不同分组间发现统计学差异（P＜0.05）。

患者外周血CD4+T 细胞、CD8+T 细胞表面PD-1 的表达率与肿瘤的不同分化程度（低分化组与中高分化组比较）成负相关，与乳腺癌TNM 分期（III/IV 期组与I/II期组比较）、淋巴结转移（有转移组与无转移组比较）、远处有转移（有远处转移组与无远处转移组比较）成正相关。

[15] 赵丹. 乳腺癌患者外周血T细胞上PD-1的表达率与临床病理参数的相关性分析[D].
（2）PD-L1 expression is an important indicator of unfavorable prognosis in breast cancer patients.
[16] Qin T , Zeng Y D , Qin G , et al. High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer[J]. Oncotarget, 2015, 6(32).
[17] Stromal PD-L1 Expression Is Associated With Better Disease-Free Survival in Triple-Negative Breast Cancer
肝细胞癌：
（1）肝癌患者PBMC 中PD-1、PD-L1 和PD-L2 分子表达增加，且PD-1、PD-L1 与IFN-γ 水平有关联，提示PD-1 和PD-L1 与肿瘤的发展以及肿瘤细胞的免疫逃逸有关。

[18] 刘伟, 柴琳, 粱军利, et al. 肝癌患者外周血CD3~+T细胞和CD19~+B细胞中程序性死亡蛋白
1(PD-1)及其配体表达水平增加[J]. 细胞与分子免疫学杂志, 2016, 32(9):1243-1247.
肠癌：
（1）结直肠癌患者血清中s PD-1 的平均表达水平[(131.14±91.91) pg/ml]高于健康志愿者[(83.07±65.47) pg/ml]，且差异具有统计学意义（P<0.05）。

结直肠癌患者外周血中CD3+T 细胞表面PD-1 的阳性表达率[(29.25±9.37)%]高于健康志愿者[(19.35±7.37)%]，差异具有显著性（P<0.01）。

且在肿瘤分化程度低、
有淋巴结转移、Dukes 分期较高的进展期结直肠癌患者外周血中PD-1 阳性表达率的上调更为明显。

[19] 吴佳茗. PD-1在结直肠癌发生发展中的表达分析及临床意义[D].
胃癌与CTLA-4
本研究同时检测了56 例胃癌患者术前外周血T 淋巴细胞表面CTLA-4 和CD28 的表达水平，胃癌患者CD3+CTLA-4+ 细胞的百分率为5.95％±1.75％，明显高于健康对照组及良性肿瘤组，P<0.01。

[20] 田玉峰, 律洁, 郑燕. 协同刺激分子CD28/CTLA-4:B7在胃癌患者中的表达及临床意义[C]// First International Conference on Cellular, molecular Biology, Biophysics & Bioengineering. .
肺癌与CTLA-4
NSCLC 患者外周血sCTLA-4 表达率高于正常人(70.7% vs 6.7%，χ2 = 32.44，P ＜0.01)，外周血sCTLA-4 增高的患者中位生存期(MST)较短(41.63 个月vs 31.57 个月，χ2 = 7.65，P ＜0.01)，死亡风险高于其他患者(RR = 3.05，χ2 = 8.01，P ＜0.01)。

NSCLC 患者外周血中sCTLA-4 高表达，sCTLA-4 可能成为晚期NSCLC 患者的预后因子之一。

CTLA-4在外周血中高表达ELISA(分别为38.43 pg /ml和25.41 pg /ml）。

[21] 吴立波, 姜怡, 姜维洁, et al. 外周血sCTLA-4作为晚期非小细胞肺癌患者的预后因子[J]. 中国
肿瘤生物治疗杂志, 2016(5):670-674.
乳腺癌与CTLA-4
[22] 李瑛. 早期乳腺癌组织和外周血中免疫相关指标检测分析研究[D]. 中国人民解放军医学院, 2015.。