4-1BB transcriptomic expression patterns across malignancies: Implications for clinical trials of 4-1BB agonists

IF 20.1 1区 医学 Q1 ONCOLOGY
Yuji Uehara, Shumei Kato, Daisuke Nishizaki, Hirotaka Miyashita, Suzanna Lee, Mary K. Nesline, Sarabjot Pabla, Jeffrey M. Conroy, Paul DePietro, Heidi Ko, Jason K. Sicklick, Razelle Kurzrock
{"title":"4-1BB transcriptomic expression patterns across malignancies: Implications for clinical trials of 4-1BB agonists","authors":"Yuji Uehara,&nbsp;Shumei Kato,&nbsp;Daisuke Nishizaki,&nbsp;Hirotaka Miyashita,&nbsp;Suzanna Lee,&nbsp;Mary K. Nesline,&nbsp;Sarabjot Pabla,&nbsp;Jeffrey M. Conroy,&nbsp;Paul DePietro,&nbsp;Heidi Ko,&nbsp;Jason K. Sicklick,&nbsp;Razelle Kurzrock","doi":"10.1002/cac2.12592","DOIUrl":null,"url":null,"abstract":"<p>4-1BB, a member of the tumor necrosis factor receptor superfamily, is an important co-stimulatory molecule regulating the activity of immune cells across a range of physiological and pathological processes, which culminates in a potent immune response (Figure 1A and B) [<span>1, 2</span>]. Numerous clinical trials have been conducted utilizing 4–1BB agonists (Supplemental Table S1); however, previous and ongoing 4-1BB agonist trials are being conducted without biomarker selection, which potentially explains their modest efficacy. Interestingly, several studies suggest the potential value of utilizing transcriptomics in addition to genomics to identify the unique immunologic signature of individual tumors [<span>3-7</span>].</p><p>Herein, we explore the landscape of 4–1BB transcriptomic profiles in 514 patients, including 489 with advanced/metastatic cancers and clinical annotation, and we discuss the potential therapeutic implications of the observed patterns and heterogeneity. The study methods are provided in the Supplementary File.</p><p>There were 514 tumors reflecting 31 different cancer types evaluated (Supplemental Table S2). Their median age was 61 (range, 24-93) years; 310 (60.3%) were women. The most frequent tumor types assessed were colorectal cancer (<i>n</i> = 140 samples). Of the 514 patients, 489 had confirmed metastatic or locally advanced disease, but the dates of metastatic disease for 25 patients were not documented. Overall, 489 patients with advanced/metastatic disease had fully evaluable clinical correlative data (Figure 1C). In total, 217 patients received ICIs; 199 received anti-programmed cell death 1 (PD-1)/ programmed death-ligand 1 (PD-L1) monotherapy, 2 received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monotherapy, and 16 received a combination of anti-PD-1/PD-L1 and anti-CTLA-4. The remaining 272 patients never received immunotherapy.</p><p>Figure 1D demonstrates the variations in 4-1BB RNA expression across different cancer types: 4-1BB ribonucleic acid (RNA) expression was classified as “high” (75-100th percentile), “moderate” (25-74th percentile), and “low” (0-24th percentile). Among all cancers (<i>n</i> = 514), 77 (15.0%) had high, 268 (52.1%) had moderate, and 169 (32.9%) had low 4-1BB expression. Small intestine and ovarian cancers most frequently had high 4-1BB RNA expression (25.0% and 20.9% of tumors, respectively).</p><p>To identify the patient population who might theoretically benefit the most from 4-1BB agonism, the proportion of patients having high 4-1BB expression along with low/moderate 4-1BB ligand (4-1BBL) expression was assessed in malignancies that had more than 20 representative samples (from a biologic point of view, high receptor with low/moderate ligand might be most amenable to treatment with 4-1BB agonists in the clinic). Malignancies with the highest proportion of patients having both high 4-1BB expression and low/moderate 4-1BBL expression were ovarian and pancreatic, with 18.6% (8/43) and 14.5% (8/55), respectively, representing the only two malignancies with &gt;15% of patients having this expression profile (Figure 1E). Otherwise, the proportions of patients having high 4-1BB expression along with low/moderate 4-1BBL expression were 12.5% (3/24) in sarcoma, 12.5% (3/24) in uterine, 10.0% (2/20) in lung, 8.0% (2/25) in stomach, 7.9% (11/140) in colorectal, and 0% (0/49) in breast. There was variability of expression patterns both within and between tumor types. It is, therefore, conceivable that patient selection for 4-1BB agonist trials based in part on transcript levels may merit investigation.</p><p>We examined 12 genes that produce immunomodulatory molecules related to the TNF receptor superfamily or interacting co-stimulatory molecules, as well as markers related to ICIs in the clinic (Supplemental Table S3). The results of the univariable and the subsequent multivariable logistic regression are shown in Figure 1F. High RNA expression of 4-1BB was not associated with any specific tumor types. Among immune markers, high 4-1BB RNA expression was significantly associated with that of PD-L2 (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.56–6.47, <i>P</i> = 0.018), ICOS (OR 4.5, 95% CI 2.03-10.36, <i>P</i> = 0.003), and CD27 (OR 2.2, 95% CI 1.12-4.81, <i>P</i> = 0.046) (all multivariable). When analyzing the pan-cancer whole genome cohort from the ICGC and TCGA (<i>n</i> = 2,658), ICOS RNA expression was the most significantly correlated with 4-1BB expression among 33,855 genes (spearman correlation coefficient (r): 0.77, <i>P</i> &lt; 0.001; Figure 1G). Although high RNA expression of 4-1BB was not associated with high PD-1/PD-L1 expression in our cohort (Figure 1F), 4-1BB RNA expression was significantly correlated with PD-1 expression when examined as a linear variable (spearman correlation coefficient: 0.70, <i>P</i> &lt; 0.001; Supplementary Figure S1). Additionally, PD-L2 and CD27 expression were also significantly correlated with 4-1BB expression (spearman correlation coefficient: 0.69, <i>P</i> &lt; 0.001; and 0.53, <i>P</i> &lt; 0.001, respectively, Figure 1G). Therefore, patients with cancer that co-expresses high PD-L2 may benefit from concomitant blocking of the immune inhibitory activity of PD-L2 if a 4-1BB agonist is given; this could be achieved by co-administering an anti-PD-1 agent since PD-L2 serves as a ligand for PD-1.</p><p>Survival outcomes were evaluable among 489 patients; among them, 272 patients never received immunotherapy, and 217 patients were treated with an immunotherapy-based regimen (Figure 1C). Among the 489 patients, the median overall survival (OS) was 51.7 months (95% CI, 43.3-61.3) for the high-4-1BB group and 35.7 months (95% CI, 30.3-44.0) for the low/moderate 4-1BB group, respectively, from the time of metastatic/advanced disease (hazard ratio [HR] = 0.74, 95%CI: 0.52-1.06, <i>P</i> = 0.103; Figure 1H). Regarding patients who never received immunotherapy, the median OS from advanced/metastatic disease was 51.7 months (95% CI, 24.4–not available [NA]) for the high-4-1BB group and 42.2 months (95% CI, 30.9-46.3) for the low/moderate 4-1BB group, respectively, from time of advanced/metastatic disease (HR = 0.83, 95%CI: 0.49-1.41, <i>P</i> = 0.497; Figure 1I).</p><p>In patients treated with immunotherapy (<i>n</i> = 217), the high 4-1BB group (<i>n</i> = 39) showed a trend towards longer progression-free survival (PFS) (HR = 0.70, 95%CI: 0.47-1.04, <i>P</i> = 0.074; Figure 1J) and significantly longer OS (HR = 0.55, 95%CI: 0.33-0.89, <i>P</i> = 0.016; Figure 1K) compared to the low/moderate 4-1BB group (<i>n</i> = 178) (calculated from start of immunotherapy). However, the significance of 4-1BB did not hold as an independent factor for survival in multivariable analysis (HR 0.83, 95% CI 0.47–1.46, <i>P</i> = 0.515; Supplemental Table S4). In contrast, in patients treated with immunotherapy, high 4-1BBL expression was not associated with longer PFS or OS (Supplementary Figure S2).</p><p>There are several limitations in this study due to its retrospective nature and limited sample size. First, although multiple types of cancer were represented, the number of patients for each type was relatively small. Secondly, our bulk analysis was not able to identify the cell types expressing 4-1BB and its ligand. In our bulk analysis, both high 4-1BB expression and high CD4/CD8 expression were observed in 10.7% of samples (Supplementary Table S5), suggesting that 4-1BB was expressed not only in T cells but also in tumor cells within the tumor microenvironment.</p><p>In summary, a myriad of reasons likely account for the suboptimal outcomes observed in current trials that focus on 4-1BB targeting. This study illuminates additional factors worth investigating in subsequent clinical trials. Based on our findings, 4-1BB and its ligand show variability of expression both between and within tumor types, indicating that cancers need to be sampled and analyzed in order to establish their individual immunomic portfolios. The concomitant high expression of 4-1BB and PD-L2 suggests that a combination approach that includes anti-PD-1 agents for malignancies with high PD-L2 expression warrants exploration.</p><p><i>Conception and design</i>: Yuji Uehara, Shumei Kato, Razelle Kurzrock. <i>Development of methodology</i>: Yuji Uehara, Shumei Kato, Daisuke Nishizaki, Razelle Kurzrock. <i>Analysis and interpretation of data</i> (e.g., statistical analysis, biostatistics, computational analysis): Yuji Uehara, Shumei Kato, Daisuke Nishizaki, Razelle Kurzrock. <i>Writing, review, and/or revision of the manuscript</i>: Yuji Uehara, Shumei Kato, Daisuke Nishizaki, Hirotaka Miyashita, Suzanna Lee, Mary K. Nesline, Sarabjot Pabla, Jeffrey M. Conroy, Paul DePietro, Heidi Ko, Jason K. Sicklick, Razelle Kurzrock. <i>Administrative, technical, or material support</i> (i.e., reporting or organizing data, constructing databases): Suzanna Lee, Shumei Kato, Daisuke Nishizaki, Razelle Kurzrock. <i>Study supervision</i>: Shumei Kato, Razelle Kurzrock.</p><p>Dr. Kato serves as a consultant for Medpace, Foundation Medicine, NeoGenomics, and CureMatch. He receives speaker's fees from Roche and Bayer, and the advisory board for Pfizer. He has research funding from ACT Genomics, Sysmex, Konica Minolta, OmniSeq, and Personalis.</p><p>Dr. Sicklick receives research funding from Novartis Pharmaceuticals, Amgen Pharmaceuticals, and Foundation Medicine; consultant fees from Grand Rounds, Loxo, and Deciphera; and speaker's fees from Roche and Deciphera. He also owns stocks in Personalis.</p><p>Dr. Kurzrock has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance and from the NCI; as well as consultant and/or speaker fees and/or advisory board/consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Datar Cancer Genetics, Daiichi, EISAI, EOM Pharmaceuticals, Iylon, LabCorp, Merck, NeoGenomics, Neomed, Pfizer, Prosperdtx, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech; has an equity interest in CureMatch Inc. and IDbyDNA; serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch. No potential conflicts of interest were disclosed by the other authors.</p><p>Dr. Kurzrock is funded in part by the National Institutes of Health (grant numbers: 5U01CA180888-08 and 5UG1CA233198-05.)</p><p>All investigations were conducted in accordance with the guidelines set by the Institutional Review Board of the University of California San Diego for data collection (Study of Personalized Cancer Therapy to Determine A Response and Toxicity, UCSD_PREDICT, NCT02478931) and all relevant investigational interventions for which the patients had provided consent.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":null,"pages":null},"PeriodicalIF":20.1000,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12592","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Communications","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cac2.12592","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

4-1BB, a member of the tumor necrosis factor receptor superfamily, is an important co-stimulatory molecule regulating the activity of immune cells across a range of physiological and pathological processes, which culminates in a potent immune response (Figure 1A and B) [1, 2]. Numerous clinical trials have been conducted utilizing 4–1BB agonists (Supplemental Table S1); however, previous and ongoing 4-1BB agonist trials are being conducted without biomarker selection, which potentially explains their modest efficacy. Interestingly, several studies suggest the potential value of utilizing transcriptomics in addition to genomics to identify the unique immunologic signature of individual tumors [3-7].

Herein, we explore the landscape of 4–1BB transcriptomic profiles in 514 patients, including 489 with advanced/metastatic cancers and clinical annotation, and we discuss the potential therapeutic implications of the observed patterns and heterogeneity. The study methods are provided in the Supplementary File.

There were 514 tumors reflecting 31 different cancer types evaluated (Supplemental Table S2). Their median age was 61 (range, 24-93) years; 310 (60.3%) were women. The most frequent tumor types assessed were colorectal cancer (n = 140 samples). Of the 514 patients, 489 had confirmed metastatic or locally advanced disease, but the dates of metastatic disease for 25 patients were not documented. Overall, 489 patients with advanced/metastatic disease had fully evaluable clinical correlative data (Figure 1C). In total, 217 patients received ICIs; 199 received anti-programmed cell death 1 (PD-1)/ programmed death-ligand 1 (PD-L1) monotherapy, 2 received anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monotherapy, and 16 received a combination of anti-PD-1/PD-L1 and anti-CTLA-4. The remaining 272 patients never received immunotherapy.

Figure 1D demonstrates the variations in 4-1BB RNA expression across different cancer types: 4-1BB ribonucleic acid (RNA) expression was classified as “high” (75-100th percentile), “moderate” (25-74th percentile), and “low” (0-24th percentile). Among all cancers (n = 514), 77 (15.0%) had high, 268 (52.1%) had moderate, and 169 (32.9%) had low 4-1BB expression. Small intestine and ovarian cancers most frequently had high 4-1BB RNA expression (25.0% and 20.9% of tumors, respectively).

To identify the patient population who might theoretically benefit the most from 4-1BB agonism, the proportion of patients having high 4-1BB expression along with low/moderate 4-1BB ligand (4-1BBL) expression was assessed in malignancies that had more than 20 representative samples (from a biologic point of view, high receptor with low/moderate ligand might be most amenable to treatment with 4-1BB agonists in the clinic). Malignancies with the highest proportion of patients having both high 4-1BB expression and low/moderate 4-1BBL expression were ovarian and pancreatic, with 18.6% (8/43) and 14.5% (8/55), respectively, representing the only two malignancies with >15% of patients having this expression profile (Figure 1E). Otherwise, the proportions of patients having high 4-1BB expression along with low/moderate 4-1BBL expression were 12.5% (3/24) in sarcoma, 12.5% (3/24) in uterine, 10.0% (2/20) in lung, 8.0% (2/25) in stomach, 7.9% (11/140) in colorectal, and 0% (0/49) in breast. There was variability of expression patterns both within and between tumor types. It is, therefore, conceivable that patient selection for 4-1BB agonist trials based in part on transcript levels may merit investigation.

We examined 12 genes that produce immunomodulatory molecules related to the TNF receptor superfamily or interacting co-stimulatory molecules, as well as markers related to ICIs in the clinic (Supplemental Table S3). The results of the univariable and the subsequent multivariable logistic regression are shown in Figure 1F. High RNA expression of 4-1BB was not associated with any specific tumor types. Among immune markers, high 4-1BB RNA expression was significantly associated with that of PD-L2 (odds ratio [OR] 3.1, 95% confidence interval [CI] 1.56–6.47, P = 0.018), ICOS (OR 4.5, 95% CI 2.03-10.36, P = 0.003), and CD27 (OR 2.2, 95% CI 1.12-4.81, P = 0.046) (all multivariable). When analyzing the pan-cancer whole genome cohort from the ICGC and TCGA (n = 2,658), ICOS RNA expression was the most significantly correlated with 4-1BB expression among 33,855 genes (spearman correlation coefficient (r): 0.77, P < 0.001; Figure 1G). Although high RNA expression of 4-1BB was not associated with high PD-1/PD-L1 expression in our cohort (Figure 1F), 4-1BB RNA expression was significantly correlated with PD-1 expression when examined as a linear variable (spearman correlation coefficient: 0.70, P < 0.001; Supplementary Figure S1). Additionally, PD-L2 and CD27 expression were also significantly correlated with 4-1BB expression (spearman correlation coefficient: 0.69, P < 0.001; and 0.53, P < 0.001, respectively, Figure 1G). Therefore, patients with cancer that co-expresses high PD-L2 may benefit from concomitant blocking of the immune inhibitory activity of PD-L2 if a 4-1BB agonist is given; this could be achieved by co-administering an anti-PD-1 agent since PD-L2 serves as a ligand for PD-1.

Survival outcomes were evaluable among 489 patients; among them, 272 patients never received immunotherapy, and 217 patients were treated with an immunotherapy-based regimen (Figure 1C). Among the 489 patients, the median overall survival (OS) was 51.7 months (95% CI, 43.3-61.3) for the high-4-1BB group and 35.7 months (95% CI, 30.3-44.0) for the low/moderate 4-1BB group, respectively, from the time of metastatic/advanced disease (hazard ratio [HR] = 0.74, 95%CI: 0.52-1.06, P = 0.103; Figure 1H). Regarding patients who never received immunotherapy, the median OS from advanced/metastatic disease was 51.7 months (95% CI, 24.4–not available [NA]) for the high-4-1BB group and 42.2 months (95% CI, 30.9-46.3) for the low/moderate 4-1BB group, respectively, from time of advanced/metastatic disease (HR = 0.83, 95%CI: 0.49-1.41, P = 0.497; Figure 1I).

In patients treated with immunotherapy (n = 217), the high 4-1BB group (n = 39) showed a trend towards longer progression-free survival (PFS) (HR = 0.70, 95%CI: 0.47-1.04, P = 0.074; Figure 1J) and significantly longer OS (HR = 0.55, 95%CI: 0.33-0.89, P = 0.016; Figure 1K) compared to the low/moderate 4-1BB group (n = 178) (calculated from start of immunotherapy). However, the significance of 4-1BB did not hold as an independent factor for survival in multivariable analysis (HR 0.83, 95% CI 0.47–1.46, P = 0.515; Supplemental Table S4). In contrast, in patients treated with immunotherapy, high 4-1BBL expression was not associated with longer PFS or OS (Supplementary Figure S2).

There are several limitations in this study due to its retrospective nature and limited sample size. First, although multiple types of cancer were represented, the number of patients for each type was relatively small. Secondly, our bulk analysis was not able to identify the cell types expressing 4-1BB and its ligand. In our bulk analysis, both high 4-1BB expression and high CD4/CD8 expression were observed in 10.7% of samples (Supplementary Table S5), suggesting that 4-1BB was expressed not only in T cells but also in tumor cells within the tumor microenvironment.

In summary, a myriad of reasons likely account for the suboptimal outcomes observed in current trials that focus on 4-1BB targeting. This study illuminates additional factors worth investigating in subsequent clinical trials. Based on our findings, 4-1BB and its ligand show variability of expression both between and within tumor types, indicating that cancers need to be sampled and analyzed in order to establish their individual immunomic portfolios. The concomitant high expression of 4-1BB and PD-L2 suggests that a combination approach that includes anti-PD-1 agents for malignancies with high PD-L2 expression warrants exploration.

Conception and design: Yuji Uehara, Shumei Kato, Razelle Kurzrock. Development of methodology: Yuji Uehara, Shumei Kato, Daisuke Nishizaki, Razelle Kurzrock. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Yuji Uehara, Shumei Kato, Daisuke Nishizaki, Razelle Kurzrock. Writing, review, and/or revision of the manuscript: Yuji Uehara, Shumei Kato, Daisuke Nishizaki, Hirotaka Miyashita, Suzanna Lee, Mary K. Nesline, Sarabjot Pabla, Jeffrey M. Conroy, Paul DePietro, Heidi Ko, Jason K. Sicklick, Razelle Kurzrock. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Suzanna Lee, Shumei Kato, Daisuke Nishizaki, Razelle Kurzrock. Study supervision: Shumei Kato, Razelle Kurzrock.

Dr. Kato serves as a consultant for Medpace, Foundation Medicine, NeoGenomics, and CureMatch. He receives speaker's fees from Roche and Bayer, and the advisory board for Pfizer. He has research funding from ACT Genomics, Sysmex, Konica Minolta, OmniSeq, and Personalis.

Dr. Sicklick receives research funding from Novartis Pharmaceuticals, Amgen Pharmaceuticals, and Foundation Medicine; consultant fees from Grand Rounds, Loxo, and Deciphera; and speaker's fees from Roche and Deciphera. He also owns stocks in Personalis.

Dr. Kurzrock has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance and from the NCI; as well as consultant and/or speaker fees and/or advisory board/consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Datar Cancer Genetics, Daiichi, EISAI, EOM Pharmaceuticals, Iylon, LabCorp, Merck, NeoGenomics, Neomed, Pfizer, Prosperdtx, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech; has an equity interest in CureMatch Inc. and IDbyDNA; serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch. No potential conflicts of interest were disclosed by the other authors.

Dr. Kurzrock is funded in part by the National Institutes of Health (grant numbers: 5U01CA180888-08 and 5UG1CA233198-05.)

All investigations were conducted in accordance with the guidelines set by the Institutional Review Board of the University of California San Diego for data collection (Study of Personalized Cancer Therapy to Determine A Response and Toxicity, UCSD_PREDICT, NCT02478931) and all relevant investigational interventions for which the patients had provided consent.

Abstract Image

不同恶性肿瘤的 4-1BB 转录组表达模式:4-1BB 激动剂临床试验的意义。
4-1BB是肿瘤坏死因子受体超家族的成员之一,它是一种重要的协同刺激分子,能调节免疫细胞在一系列生理和病理过程中的活性,最终产生强有力的免疫反应(图1A和B)[1, 2]。利用 4-1BB 激动剂进行的临床试验不胜枚举(补充表 S1);然而,以往和正在进行的 4-1BB 激动剂试验都是在未选择生物标记物的情况下进行的,这可能是其疗效一般的原因。有趣的是,一些研究表明,除了基因组学外,利用转录组学来识别个体肿瘤的独特免疫学特征也具有潜在价值[3-7]。在此,我们探讨了 514 例患者(包括 489 例晚期/转移性癌症患者和临床注释患者)的 4-1BB 转录组特征,并讨论了所观察到的模式和异质性的潜在治疗意义。研究方法见补充文件。514例肿瘤反映了31种不同的癌症类型(补充表S2)。中位年龄为 61 岁(24-93 岁不等),女性 310 人(60.3%)。最常评估的肿瘤类型是结直肠癌(n = 140 个样本)。在 514 名患者中,489 人已确诊为转移性或局部晚期疾病,但 25 名患者的转移性疾病发生日期没有记录。总体而言,489 名晚期/转移性疾病患者拥有完全可评估的临床相关数据(图 1C)。共有 217 名患者接受了 ICIs;其中 199 人接受了抗程序性细胞死亡 1(PD-1)/程序性死亡配体 1(PD-L1)单药治疗,2 人接受了抗细胞毒性 T 淋巴细胞相关蛋白 4(CTLA-4)单药治疗,16 人接受了抗 PD-1/PD-L1 和抗 CTLA-4 联合治疗。图1D显示了不同癌症类型中4-1BB RNA表达的变化:4-1BB核糖核酸(RNA)表达分为 "高"(75-100百分位数)、"中"(25-74百分位数)和 "低"(0-24百分位数)。在所有癌症(n = 514)中,77 例(15.0%)4-1BB 高表达,268 例(52.1%)中度表达,169 例(32.9%)低表达。小肠癌和卵巢癌最常出现 4-1BB RNA 高表达(分别占肿瘤的 25.0% 和 20.9%)。为了确定理论上可能从4-1BB激动剂中获益最多的患者人群,我们在有20个以上代表性样本的恶性肿瘤中评估了4-1BB高表达同时4-1BB配体(4-1BBL)低/中表达的患者比例(从生物学角度来看,高受体低/中配体可能最适合在临床上使用4-1BB激动剂治疗)。4-1BB高表达和4-1BBL低/中表达患者比例最高的恶性肿瘤是卵巢癌和胰腺癌,分别为18.6%(8/43)和14.5%(8/55),这两种恶性肿瘤中只有&gt;15%的患者具有这种表达特征(图1E)。此外,4-1BB高表达同时4-1BBL低/中度表达的患者比例分别为:肉瘤12.5%(3/24)、子宫癌12.5%(3/24)、肺癌10.0%(2/20)、胃癌8.0%(2/25)、结直肠癌7.9%(11/140)、乳腺癌0%(0/49)。肿瘤类型内部和之间的表达模式存在差异。我们研究了产生与 TNF 受体超家族相关的免疫调节分子或相互作用的共刺激分子的 12 个基因,以及与临床 ICIs 相关的标记物(补充表 S3)。单变量和随后的多变量逻辑回归结果见图 1F。4-1BB的高RNA表达与任何特定肿瘤类型无关。在免疫标记物中,4-1BB RNA高表达与PD-L2(几率比[OR]3.1,95%置信区间[CI]1.56-6.47,P = 0.018)、ICOS(OR 4.5,95% CI 2.03-10.36,P = 0.003)和CD27(OR 2.2,95% CI 1.12-4.81,P = 0.046)显著相关(均为多变量)。在分析来自 ICGC 和 TCGA 的泛癌症全基因组队列(n = 2,658)时,在 33,855 个基因中,ICOS RNA 表达与 4-1BB 表达的相关性最为显著(矛曼相关系数 (r):0.77, P &lt; 0.001; 图 1G)。虽然在我们的队列中,4-1BB 的高 RNA 表达与 PD-1/PD-L1 的高表达无关(图 1F),但如果将 4-1BB 的 RNA 表达作为线性变量进行研究,则其与 PD-1 的表达显著相关(spearman 相关系数:0.70,P &lt; 0.001;补充图 S1)。此外,PD-L2 和 CD27 的表达也与 4-1BB 的表达显著相关(矛人相关系数:0.69,P &lt;0.001;0.53,P &lt;0.001)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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