四月week4文獻(xiàn)閱讀1：Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy

基于阻斷的PD-1檢查點(diǎn)的免疫治療泛腫瘤基因組生物標(biāo)志物

INTRODUCTION：

Immunotherapy targeting the programmed cell death protein–1 (PD-1) axis elicits durable antitumor responses in multiple cancer types.

針對程序性細(xì)胞死亡蛋白-1 (PD-1)軸的免疫治療可在多種癌癥類型中引起持久的抗腫瘤反應(yīng)。

However, clinical responses vary, and biomarkers predictive of response may help to identify patients who will derive the greatest therapeutic benefit.

然而舆床，臨床反應(yīng)不同，生物標(biāo)志物預(yù)測反應(yīng)可能有助于確定誰將獲得最大的治療效益。

Clinically validated biomarkers predictive of response to the anti–PD-1 monoclonal antibody pembrolizumab include PD-1 ligand 1 (PD-L1) expression in specific cancers and high microsatellite instability (MSI-H) regardless of tumor type.

臨床驗(yàn)證的預(yù)測抗PD-1單克隆抗體pembrolizumab反應(yīng)的生物標(biāo)志物包括PD-1配體1 (PD-L1)在特定癌癥中的表達(dá)以及無論腫瘤類型如何的高的微衛(wèi)星不穩(wěn)定性(MSI-H)移斩。

Tumor mutational burden (TMB) and T cell–inflamed gene expression profile (GEP) are emerging predictive biomarkers for pembrolizumab.

腫瘤突變負(fù)擔(dān)(TMB)和T細(xì)胞炎癥基因表達(dá)譜(GEP)是pembrolizumab新的預(yù)測生物標(biāo)志物注盈。

Both PD-L1 and GEP are inflammatory biomarkers indicative of a T cell–inflamed tumor microenvironment (TME), whereas TMB and MSI-H are indirect measures of tumor antigenicity generated by somatic tumor mutations.

PD-L1和GEP都是T細(xì)胞炎癥性腫瘤微環(huán)境(TME)的炎癥標(biāo)志物撇吞，而TMB和MSI-H則是由體細(xì)胞腫瘤突變產(chǎn)生的腫瘤抗原性的間接指標(biāo)。

However, the relationship between these two categories of biomarkers is notwell characterized.

然而魄健，這兩類生物標(biāo)志物之間的關(guān)系還沒有很好地描述。

名詞解釋：
PD-1配體1 (PD-L1)在特定癌癥中的表達(dá)插勤，T細(xì)胞炎癥基因表達(dá)譜(GEP)沽瘦。
腫瘤突變負(fù)擔(dān)(TMB)，高的微衛(wèi)星不穩(wěn)定性(MSI-H)农尖。
PD-L1和GEP都是T細(xì)胞炎癥性腫瘤微環(huán)境(TME)的炎癥標(biāo)志物析恋，而TMB和MSI-H則是由體細(xì)胞腫瘤突變產(chǎn)生的腫瘤抗原性的間接指標(biāo)。

RATIONALE 理論依據(jù)

This study assessed the potential for TMB and a T cell–inflamed GEP to jointly predict clinical response to pembrolizumab in >300 patient samples with advanced solid tumors and melanoma across 22 tumor types from four KEYNOTE clinical trials.

本研究評估了TMB和T細(xì)胞炎癥性GEP聯(lián)合預(yù)測pembrolizumab在>300例晚期實(shí)體瘤和黑色素瘤患者中的臨床反應(yīng)的潛力盛卡，這些患者來自4個(gè)主要臨床試驗(yàn)的22種腫瘤類型助隧。

To assess the individual and joint clinical utility of TMB and GEP, patients were stratified in four biomarker-defined clinical response groups [GEP low and TMB low (GEPlo TMBlo),GEP low and TMB high (GEPlo TMBhi), GEPhi TMBlo, and GEPhi TMBhi] based on predefined cutoffs for TMB and GEP.

為了評估TMB和GEP的個(gè)體和聯(lián)合臨床效用，根據(jù)預(yù)先定義的TMB和GEP的截?cái)嘀祷祝瑢⒒颊叻譃樗膫€(gè)生物標(biāo)志物定義的臨床反應(yīng)組[GEP低和TMB低(GEPlo TMBlo)并村，GEP低和TMB高(GEPlo TMBhi)， GEP高TMB低和GEPhi TMBhi]滓技。

These patient-defined biomarker groups were further used to guide transcriptome and exome analyses of tumors in a large molecular database [The Cancer Genome Atlas (TCGA)] (n = 6384 tumors) to identify targetable patterns of biology that may modulate response and resistance.

這些患者定義的生物標(biāo)志物組進(jìn)一步用于指導(dǎo)大分子數(shù)據(jù)庫中腫瘤的轉(zhuǎn)錄組和外顯體分析[癌癥基因組圖譜(TCGA)] (n = 6384個(gè)腫瘤)哩牍，以確定可能調(diào)節(jié)反應(yīng)和耐藥性的生物學(xué)靶標(biāo)模式。

RESULTS:

TMB and GEP exhibited only modest correlation and were independently predictive of response across the KEYNOTE clinical datasets.

TMB和GEP僅表現(xiàn)出適度的相關(guān)性令漂，并獨(dú)立預(yù)測基調(diào)臨床數(shù)據(jù)集的反應(yīng)姐叁。

We found that objective response rates were strongest in patients with GEPhi TMBhi (37 to 57%), moderate in those with GEPhi TMBlo (12 to 35%) and GEPlo TMBhi (11 to 42%), and reduced or absent in those with GEPlo TMBlo (0 to 9%) (see the figure).

我們發(fā)現(xiàn)，GEP高 TMB高患者的客觀反應(yīng)率最高(37 - 57%)，GEP高 TMB低患者的客觀反應(yīng)率最低(12 - 35%)外潜，GEP低TMB高患者的客觀反應(yīng)率最低(11 - 42%)原环，GEP低 TMB低患者的客觀反應(yīng)率最低(0 - 9%)(見圖)。

Additionally, longer progression-free survival times were seen in patients with higher levels of both TMB and GEP.

此外处窥，TMB和GEP水平較高的患者無進(jìn)展生存時(shí)間更長嘱吗。

Findings were comparable when TMB and PD-L1 expression were jointly assessed.

聯(lián)合評估TMB和PD-L1表達(dá)時(shí)，結(jié)果具有可比性滔驾。

Within TCGA database,GEP and TMB again had a low correlation, demonstrating the potential to jointly stratify transcriptomic and genomic features across cancer types.

在TCGA數(shù)據(jù)庫中谒麦，GEP和TMB再次具有較低的相關(guān)性，顯示了跨癌癥類型聯(lián)合分層轉(zhuǎn)錄組和基因組特征的潛力哆致。

Specific gene expression patterns reflective of TME biology showed significant associations with TMB, GEP, or both.

反映TME生物學(xué)的特定基因表達(dá)模式與TMB绕德、GEP或兩者均有顯著關(guān)聯(lián)。

In particular, gene set enrichment analysis identified proliferative and stromal, myeloid, and vascular biology corresponding to specific TMB-defined subgroups within GEPhi tumors.

特別是摊阀，基因集富集分析確定了與GEP高腫瘤中特定TMB定義的亞群相對應(yīng)的增殖和基質(zhì)耻蛇、髓細(xì)胞和血管生物學(xué)。

In TMBhi tumors, indication-dependent somatic DNA alterations in key cancer driver genes showed a strong negative association with GEP.

在TMB高腫瘤中胞此，關(guān)鍵腫瘤驅(qū)動(dòng)基因的指示依賴性體細(xì)胞DNA改變與GEP呈顯著負(fù)相關(guān)臣咖。

CONCLUSION:

This analysis shows that TMB and inflammatory biomarkers (T cell–inflamed GEP and PD-L1 expression) can jointly stratify human cancers into groups with different clinical responses to pembrolizumab monotherapy and identify patterns of underlying, targetable biology related to these groups.

這一分析表明，TMB和炎癥生物標(biāo)志物(T細(xì)胞炎癥性GEP和PD-L1表達(dá))可以聯(lián)合將人類癌癥分為對pembrolizumab單藥治療有不同臨床反應(yīng)的組漱牵，并識(shí)別與這些組相關(guān)的潛在的夺蛇、可靶向的生物學(xué)模式。

TMB and inflammatory biomarkers independently predict response and may capture distinct features of neoantigenicity and T cell activation, respectively.

TMB和炎癥生物標(biāo)志物可以獨(dú)立預(yù)測反應(yīng)酣胀，并可能分別捕捉到新抗原性和T細(xì)胞活化的不同特征刁赦。

This approach may provide a precision medicine framework for rationally constructing and evaluating anti–PD-1– and/or –PD-L1–based combination therapy regimens.

該方法可為合理構(gòu)建和評價(jià)抗pd -1和/或- pd - l1聯(lián)合治療方案提供精確的醫(yī)學(xué)框架。

Abstract

Programmed cell death protein–1 (PD-1) and programmed cell death ligand–1 (PD-L1) checkpoint blockade immunotherapyelicits durable antitumoreffects in multiple cancers, yet not all patients respond.

程序性細(xì)胞死亡蛋白-1 (PD-1)和程序性細(xì)胞死亡配體-1 (PD-L1)檢查點(diǎn)阻斷免疫治療在多種癌癥中具有持久的抗腫瘤作用闻镶，但并非所有患者都有反應(yīng)截型。

We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials.

我們報(bào)告了來自四個(gè)主要臨床試驗(yàn)的22種腫瘤類型的>300例患者樣本的評估。

Tumor mutational burden (TMB) and a Tcell–inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab.

腫瘤突變負(fù)擔(dān)(TMB)和t細(xì)胞炎癥基因表達(dá)譜(GEP)在識(shí)別PD-1抗體pembrolizumab應(yīng)答者和無應(yīng)答者方面顯示出聯(lián)合預(yù)測作用儒溉。

TMB and GEP were independently predictive of response and demonstrated low correlation,suggesting that they capture distinct features of neoantigenicity and T cell activation.

TMB和GEP對反應(yīng)具有獨(dú)立的預(yù)測作用宦焦，且相關(guān)性較低，說明它們捕獲了新抗原性和T細(xì)胞活化的不同特征顿涣。

Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology.

對腫瘤基因組圖譜數(shù)據(jù)庫的分析表明波闹，TMB與GEP相關(guān)性較低，聯(lián)合分層分析揭示了生物標(biāo)志物所定義的靶向性生物學(xué)模式涛碑。

These biomarkers may have utility in clinical trial design by guiding rational selection of anti–PD-1 monotherapy and combination immunotherapy regimens.

這些生物標(biāo)志物可指導(dǎo)抗pd -1單藥和聯(lián)合免疫治療方案的合理選擇精堕，在臨床試驗(yàn)設(shè)計(jì)中具有實(shí)用價(jià)值。

(TMB和GEP對反應(yīng)具有獨(dú)立的預(yù)測,或聯(lián)合預(yù)測蒲障，腫瘤突變負(fù)擔(dān)(TMB)和t細(xì)胞炎癥基因表達(dá)譜(GEP)在識(shí)別PD-1抗體pembrolizumab歹篓，預(yù)測抗PD-1單克隆抗體pembrolizumab反應(yīng)瘫证，應(yīng)答者和無應(yīng)答者（客觀反應(yīng)率），相關(guān)性函數(shù)庄撮，各指標(biāo)輸入后的預(yù)測的反應(yīng)結(jié)果（反應(yīng)率的等級劃分）)

• Emerging immune-relevant biomarkers for checkpoint blockade immunotherapy response can be placed broadly into two categories: those related to tumor neoepitope burden, such as microsatellite instability (MSI) or high tumor mutational burden (TMB), and those indicative of a T cell–inflamed tumor microenvironment (TME).

  檢查點(diǎn)阻斷免疫治療反應(yīng)的新興免疫相關(guān)生物標(biāo)志物可大致分為兩類:一類是與腫瘤新表位負(fù)擔(dān)相關(guān)的生物標(biāo)志物背捌，如微衛(wèi)星不穩(wěn)定性(MSI)或高腫瘤突變負(fù)擔(dān)(TMB)，另一類是提示T細(xì)胞炎癥性腫瘤微環(huán)境(TME)洞斯。

• The latter include programmed cell deathlig and–1(PD-L1)protein expression on tumor and immune cells, which in many cases is up-regulated in response to local T cell– derived interferon-g (IFN-g),and gene signatures of activated T cells (1–3).

  后者包括腫瘤細(xì)胞和免疫細(xì)胞上的程序性細(xì)胞死亡配體- 1(PD-L1)蛋白表達(dá)毡庆，在許多情況下，這種蛋白表達(dá)會(huì)隨著局部T細(xì)胞來源的干擾素-g (IFN-g)和活化T細(xì)胞的基因信號(hào)而上調(diào)(1-3)烙如。

• TMB is correlated with clinical response to cytotoxic T lymphocyte– associated antigen–4 blockade in advanced melanoma (4–6) and with anti–programmed cell deathprotein–1(PD-1)and/orPD-L1blockadein melanoma(7),non–smallcelllungcancer(NSCLC) (8, 9), colorectal and gastric cancers (10, 11), and urothelialcancer (12).

  TMB與晚期黑色素瘤(4-6)中細(xì)胞毒性T淋巴細(xì)胞相關(guān)抗原- 4阻斷的臨床反應(yīng)相關(guān)么抗，與抗程序性細(xì)胞死亡蛋白-1 (PD-1)和/orPD-L1blockadein黑色素瘤(7)、非小細(xì)胞肺癌(8,9)亚铁、結(jié)直腸癌和胃癌(10,11)蝇刀、泌尿系癌(12)相關(guān)。

• Similarly, tumors with MSI thathavehighlevelsofbothsingle-nucleotideand frameshift mutations [high MSI (MSI-H)] are responsive to anti–PD-1 therapy in colorectal cancer and other malignancies (10, 11).

  同樣徘溢，MSI高水平單核苷酸和移碼突變[高M(jìn)SI (MSI- h)]的腫瘤對結(jié)直腸癌和其他惡性腫瘤的抗pd -1治療也有反應(yīng)(10,11)吞琐。

  Expression of genes related to immunecytolytic activity have also been shown to be associated with clinical response to checkpoint blockade in certain tumors (13, 14).

  與免疫溶細(xì)胞活性相關(guān)的基因表達(dá)也被證明與某些腫瘤對檢查點(diǎn)阻斷的臨床反應(yīng)有關(guān)(13,14)。

  Recently, a T cell–inflamed gene expression profile (GEP) was shown to predict response to anti–PD-1–directed therapy (15).

  最近甸昏，T細(xì)胞炎癥基因表達(dá)譜(GEP)被證明可以預(yù)測抗pd -1定向治療的反應(yīng)(15)。

• However,the inter play between these two distinct categories of biomarkers has not been well characterized across cancer types with respect to their ability either to independently or jointly predict response to immunotherapy or to reveal underlying genomic and/or transcriptomic features of tumor antigenicity and TME.

  然而徐许，這兩種截然不同的生物標(biāo)志物之間的相互作用還沒有被很好地跨類型描述施蜜，因?yàn)樗鼈兗饶塥?dú)立又能共同預(yù)測免疫治療的反應(yīng)，也能揭示腫瘤抗原性和TME的潛在基因組和/或轉(zhuǎn)錄組特征雌隅。

• We evaluated the relation ship between somatic TMB and clinical response to anti–PD-1 immuno therapy with pembrolizumab.

  我們評估了軀體TMB與pembrolizumab抗pd -1免疫治療的臨床反應(yīng)之間的關(guān)系翻默。

• Twenty-twocancer types were included in the discovery and validation cohorts and were analyzed for the independent and joint predictive values of TMB and T cell –inflamed GEP.

  在發(fā)現(xiàn)和驗(yàn)證組中納入了20種腫瘤類型，并分析了TMB和T細(xì)胞炎癥性GEP的獨(dú)立和聯(lián)合預(yù)測值恰起。

• Additionally, by using large molecular databases [e.g.

  此外修械，通過使用大型分子數(shù)據(jù)庫[例如。

• The Cancer Genome Atlas (TCGA) (16)],we explored transcriptomic and genetic features associated with the presence or absence of either of these two markers.

  在癌癥基因組圖譜(TCGA)(16)中检盼，我們探索了存在或不存在這兩種標(biāo)記的轉(zhuǎn)錄組學(xué)和遺傳學(xué)特征肯污。

Study cohorts and tumor and mutation type

研究群體、腫瘤和突變類型

• The predictive values of TMB and the T cell– inflamed GEP were first assessed separately by rigorous stepwise testing in four cohorts of patients across the pembrolizumab clinical development program (one discovery, one pan-tumor validation, and two single-indication summary cohorts).

  分別評估TMB和T細(xì)胞炎癥性GEP的預(yù)測值吨枉，首先通過嚴(yán)格的逐步測試四組患者在pembrolizumab臨床發(fā)展項(xiàng)目(一個(gè)發(fā)現(xiàn)蹦渣、一個(gè)泛腫瘤驗(yàn)證和兩個(gè)單指征總結(jié)組)。

• TMB was evaluated by whole-exome sequencing (WES) of germline and tumor DNA, and the T cell–inflamed GEP was analyzed by targeted gene expression profiling of tumor RNA (with the NanoString platform) from formalinfixed, paraffin-embedded (FFPE) pretreatment samples.

采用生殖系和腫瘤DNA全外顯子組測序(WES)評價(jià)TMB貌亭，采用石蠟包埋(FFPE)預(yù)處理樣品腫瘤RNA靶向基因表達(dá)譜(NanoString platform)分析T細(xì)胞感染的GEP柬唯。

The initial discovery cohort for TMB comprised patients with PD-L1–positive head and neck squamous cell carcinoma (HNSCC) from a phase 1b clinical trial (KEYNOTE-012 B1 cohort;n = 34 patients), and the pan-tumor validation cohort consisted of patients with PD-L1–positive advanced solid tumors (n = 119 patients) from two multi cohort phase 1b trials across 20 cancer types[KEYNOTE-028(17cohorts;n=80patients) and KEYNOTE-012 (A, C, and D cohorts;n = 39 patients)].

初始發(fā)現(xiàn)TMB隊(duì)列由PD-L1-positive患者頭頸部鱗狀細(xì)胞癌(HNSCC) 1 b期臨床試驗(yàn)(主題- 012 B1組;n = 34名患者),和pan-tumor驗(yàn)證隊(duì)列由PD-L1-positive的實(shí)體腫瘤患者(n = 119例)從兩個(gè)多隊(duì)列1 b階段試驗(yàn)20個(gè)癌癥類型(主題- 028(17組;n = 80名患者)和主題- 012 (a, C和D組,n = 39病人)]。

The HNSCC single-indication cohort (n=107patients)include dpatients in the phase 1b KEYNOTE-012 B1 cohort and additional patientswithPD-L1–unselected HNSCC(n=73patients) from the KEYNOTE-012 B2 cohort.

HNSCC單指征隊(duì)列(n=107例患者)包括1b期KEYNOTE-012 B1組患者和來自KEYNOTE-012 B2組的pd - l1 -未選HNSCC患者(n=73例患者)圃庭。

The melanoma single-indication cohort included patients with advanced melanoma from the phase 1b(KEYNOTE-001;n=30patients)and the phase 3 (KEYNOTE-006 pembrolizumab arm;n = 59 patients)trials.

黑色素瘤單指征隊(duì)列包括來自1b期(KEYNOTE-001;n=30例)和3期(KEYNOTE-006 pembrolizumab arm;n = 59例)試驗(yàn)的晚期黑色素瘤患者锄奢。

The clinical characteristics of each cohort are listed in table S1, and the characteristics of all patients included in this study are listed in table S2.

各隊(duì)列的臨床特征見表S1失晴，本研究納入的所有患者的臨床特征見表S2。

The distribution of tumor mutational signatures across the study cohorts largely reflected recognized cancer subtype–dependent determinants of mutagenesis (17) (table S3 and fig. S1).

整個(gè)研究群體中腫瘤突變特征的分布在很大程度上反映了突變的公認(rèn)的癌癥亞型依賴性決定因素(17)(表S3和圖S1)拘央。

The dominant mutational signatures varied across tumor types in the pan-cancer cohort, with higher TMB associated with tissue-specific signatures, such as smoking in small cell lung cancer;apolipoprotein B mRNA editing enzyme, catalytic polypeptide–like (APOBEC) in genitourinary tumors;and mismatch repair (MMR) in gastrointestinal cancer.

顯性突變簽名在pan-cancer隊(duì)列中腫瘤類型多樣,具有較高TMB與組織相關(guān)的特征,如吸煙在小細(xì)胞肺癌;載脂蛋白B信使rna編輯酶,催化polypeptide-like (APOBEC)在泌尿系腫瘤;和錯(cuò)配修復(fù)(MMR)在胃腸道癌癥涂屁。

Dominant signatures in the single-indication cohorts were more homogenous,with an APOBEC signature in the HNSCC cohort (61% of tumors) and an ultraviolet (UV) light exposure signature in melanoma (in 78% of the tumors, >30% of mutations were UV light induced).

單指征組的優(yōu)勢特征更為均勻，在HNSCC組中有APOBEC特征(61%的腫瘤)堪滨，在黑色素瘤中有紫外(UV)照射特征(78%的腫瘤中胯陋，30%的突變是由紫外線誘導(dǎo)的)。

Association of TMB and Tcell–inflamed GEP with clinical response

TMB和t細(xì)胞炎癥性GEP與臨床反應(yīng)的關(guān)系

• Clinical response associations were assessed on the basis of best overall response (BOR) and progression-free survival (PFS) by RECIST 1.1.

  根據(jù)RECIST 1.1的最佳總體反應(yīng)(BOR)和無進(jìn)展生存(PFS)評估臨床反應(yīng)相關(guān)性袱箱。

  （總體反應(yīng)和無進(jìn)展的什么具體指標(biāo)被定為有反應(yīng)和無反應(yīng)遏乔？）

• BOR and PFS associations with TMB and the Tcell–inflamed GEP were assessed in all patients who had WES and transcriptomic data available

  在所有有WES和轉(zhuǎn)錄組數(shù)據(jù)的患者中評估BOR和PFS與TMB和tcell炎癥性GEP的關(guān)系

  We first assessed the predictive value of each individual genomic biomarker separately across the different cohorts.

  我們首先評估了不同群體中每個(gè)單獨(dú)的基因組生物標(biāo)志物的預(yù)測價(jià)值。

• In the HNSCCB1 discovery cohort,higher TMB predicted a greater frequency of clinical response (BOR) (P = 0.0123).

  在HNSCCB1發(fā)現(xiàn)隊(duì)列中发笔，較高的TMB預(yù)示著更高的臨床反應(yīng)頻率(BOR) (P = 0.0123)盟萨。

• This was validated by using the pan-tumor cohort,in which TMB was again associated with BOR (P < 0.001) (Fig.1A).

  這是通過使用泛腫瘤隊(duì)列證實(shí)的，其中TMB再次與BOR相關(guān)(P < 0.001)(圖1A)了讨。

  Higher Tcell–inflamed GEP scores were also positively associated with BOR in the pan-tumorcohort(P<0.01)(Fig.1B),showing that a T cell –activated tumor environment also affects response in addition to TMB.

  在泛腫瘤隊(duì)列中捻激，T細(xì)胞炎癥性GEP評分較高也與BOR呈正相關(guān)(P<0.01)(圖1B)，這表明T細(xì)胞激活的腫瘤環(huán)境除了影響TMB外前计，還影響反應(yīng)胞谭。

  
  
  fig1AB

• Similarly,both TMB and T cell–inflamed GEP scores were positively associated with BOR in the single-indication cohorts of HNSCC (P < 0.05 and P < 0.001, respectively) and melanoma (P < 0.05 for both) patients (Fig.1,AandB).

  同樣，在HNSCC單指征組(P < 0.05, P < 0.001)和黑色素瘤(P < 0.05)患者中男杈，TMB和T細(xì)胞炎癥性GEP評分均與BOR呈正相關(guān)(圖1丈屹、AandB)。

  In this study,we did not evaluate the effect of human papillomavirus (HPV)antigens on the association of TMB with response in the HNSCC cohort;however,we have previously described the association of TMB with clinical outcome in a larger, overlapping group of HNSCC patients (KEYNOTE-012 B1 and B2 cohorts)stratified by HPV status(18).

  在這項(xiàng)研究中,我們沒有評估的影響人類乳頭狀瘤病毒(HPV)抗原的聯(lián)合與TMB響應(yīng)在HNSCC隊(duì)列反應(yīng);然而,我們曾描述了在一個(gè)更大的,重疊群HNSCC病人(主題- 012 B1和B2組)分層的人乳頭狀瘤病毒狀態(tài)(18)TMB 的與臨床結(jié)果的結(jié)合伶棒。

  Although we found that TMB was more strongly associated with BOR in HPV-negative patients than in HPV positive patients,those exploratory findings await validation in larger, independent studies

  雖然我們發(fā)現(xiàn)TMB在HPV陰性患者中與BOR的相關(guān)性比在HPV陽性患者中更強(qiáng)旺垒，但這些探索性的發(fā)現(xiàn)有待更大規(guī)模的獨(dú)立研究的驗(yàn)證

  The clinical utility of TMB in predicting BOR was generally high, and degrees of utility were similar across cancer types,with areas under the receiveroperatingcharacteristiccurves(AUROCs) of 0.740, 0.617, and 0.602 in the pan-tumor, HNSCC, and melanoma cohorts, respectively.

  TMB在預(yù)測BOR方面的臨床實(shí)用價(jià)值普遍較高，不同癌癥類型的實(shí)用程度相似肤无，在泛腫瘤先蒋、HNSCC和黑色素瘤患者中，接受手術(shù)特征曲線(AUROCs)下的區(qū)域分別為0.740宛渐、0.617和0.602竞漾。

  Similar results were observed for the T cell– inflamed GEP across the cohorts (AUROCs = 0.782,0.768,and0.638,respectively)(Fig.1C).

  各組T細(xì)胞炎癥性GEP的結(jié)果相似(AUROCs = 0.782,0.768, 0.638)(圖1c)。

  The potential performance of a targeted sequencing– based TMB assay was simulated by using the genes in the Foundation Medicine targeted sequencing platform(19).The corresponding AUROC across the cohorts was comparable to that observed by usingWES(0.721),suggesting potential translatability to a targeted panel diagnostic.

  利用基礎(chǔ)醫(yī)學(xué)靶向測序平臺(tái)(19)中的基因窥翩，模擬了基于靶向測序的TMB檢測的潛在性能與各組中相應(yīng)的AUROC值與WES觀察值相當(dāng)(0.721)畴蹭，表明其潛在的可譯性可用于靶板診斷。

  Taken together,these data imply that both TMB and the Tcell–inflamed GEP have comparable performance characteristics and potential diagnostic utility

  綜上所述鳍烁，這些數(shù)據(jù)表明TMB和tcell炎癥性GEP具有相似的性能特征和潛在的診斷價(jià)值

We next evaluated the joint utility of the two genomic biomarkers in predicting response.

接下來叨襟，我們評估了這兩種基因組生物標(biāo)志物在預(yù)測反應(yīng)中的聯(lián)合效用。

The correlation between TMB and GEP was low in the pan-tumor and melanoma cohorts(Spearman correlation coefficient r = 0.221, P < 0.05, andr = 0.252, P < 0.05, respectively), and there was no correlation in the HNSCC cohort (r =?0.020, P = 0.841)(Fig.2A).

在泛腫瘤組和黑色素瘤組中幔荒，TMB與GEP的相關(guān)性較低(Spearman相關(guān)系數(shù)r = 0.221, P < 0.05, r = 0.252, P < 0.05)糊闽，在HNSCC組中無相關(guān)性(r = - 0.020, P = 0.841)(圖2a)梳玫。

fig2AB

This lack of correlation,combined with the observed individual predictive values, suggested that TMB and theTcell–inflamed GEP are independent predictive measures of response to pembrolizumab.

這種相關(guān)性的缺乏，結(jié)合觀察到的個(gè)體預(yù)測值右犹，表明TMB和tcell炎癥的GEP是對pembrolizumab反應(yīng)的獨(dú)立預(yù)測措施提澎。

When tested in a multivariate model adjusted for each measure, both TMB and T cell–inflamed GEP retained significant predictive value in the pan-tumor(P=0.0028and0.0051, respectively) and HNSCC (P = 0.0013 and 0.0004) cohorts, whereas only GEP remained significant in the melanoma cohort (P = 0.1644 and 0.026).

在對每一項(xiàng)指標(biāo)進(jìn)行調(diào)整的多元模型中進(jìn)行測試時(shí)，TMB和T細(xì)胞炎癥性GEP在泛腫瘤(P=0.0028和0.0051)和HNSCC (P= 0.0013和0.0004)組中均保留了顯著的預(yù)測價(jià)值念链，而在黑色素瘤組中只有GEP保持顯著的預(yù)測價(jià)值(P= 0.1644和0.026)盼忌。

Although a portion of the patients in this study were PD-L1 selected, these relationships were observed even in those cohorts of patients that were not PD-L1 selected.

雖然本研究中有一部分患者選擇PD-L1，但即使在未選擇PD-L1的患者中也觀察到了這些關(guān)系掂墓。

• We evaluated the association of the genomic biomarkers with PD-L1 immunohistochemistry (IHC) scores (fig. S2).

  我們評估了基因組生物標(biāo)志物與PD-L1免疫組化(IHC)評分的相關(guān)性(圖S2)谦纱。

  TMB was significantly but moderately correlated with PD-L1 in the pan tumor cohort[combinedpositivescore(CPS),r= 0.330;P = 0.0038] and showed no association withPD-L1 in the HNSCC cohort(CPS, r=0.020;P = 0.8084) or in the melanoma cohort [melanoma (MEL) score, r = 0.049;P = 0.6473].

  在泛腫瘤隊(duì)列中，TMB與PD-L1顯著但中度相關(guān)[聯(lián)合陽性(CPS)君编，r= 0.330;P = 0.0038]跨嘉，在HNSCC隊(duì)列中，TMB與PD-L1無相關(guān)性(CPS, r=0.020;或在黑色素瘤隊(duì)列中[黑色素瘤(MEL)評分吃嘿，r = 0.049;P = 0.6473)祠乃。

  In contrast, GEP was more significantly correlated with PD-L1 in the pan-tumor, HNSCC, and melanoma cohorts (r = 0.49, 0.51, and 0.53, respectively;all P values < 0.001), consistent with the known regulation of PD-L1 gene expression by T cell–derived IFN-g (1–3).

  相比之下，GEP與泛腫瘤組兑燥、HNSCC組和黑色素瘤組PD-L1的相關(guān)性更顯著(r分別為0.49亮瓷、0.51和0.53;所有P值均< 0.001)，與T細(xì)胞來源的IFN-g調(diào)控PD-L1基因表達(dá)的已知規(guī)律一致(1-3)降瞳。

  This correlation suggests that a PD-L1 IHC–based assay is relevant in assessing a T cell–inflamed TME.

  這種相關(guān)性表明嘱支，基于PD-L1 IHC的檢測與評估T細(xì)胞感染的TME有關(guān)。

  As seen with high TMB(TMBhi) and high GEP scores (GEPhi), responses in patients who had both TMBhi and greater PD-L1 expression (PD-L1+;CPS≥1) were greater than those in patients who had low levels of both TMB and PD-L1 expression.

  從高TMB(TMBhi)和高GEP評分(GEPhi)可以看出力崇，TMB高和PD-L1表達(dá)(PD-L1+)同時(shí)存在的患者的反應(yīng);CPS≥1)明顯高于TMB和PD-L1表達(dá)水平較低的患者斗塘。

• We next studied the potential joint utility of TMB and GEP for patient stratification and treatment outcome prediction.

  接下來赢织，我們研究了TMB和GEP在患者分層和治療結(jié)果預(yù)測方面的潛在聯(lián)合應(yīng)用亮靴。

  Clinical response was evaluated on the basis of cut points associated with the Youden Index (derived from the AUROCs for TMB in each cohort) and a discovery cutoff of ?0.318 for the T cell–inflamed GEP score (selected via analysis of pan-cancer data) (15).

  臨床反應(yīng)的評估基于與Youden指數(shù)相關(guān)的切點(diǎn)(來自每個(gè)隊(duì)列中TMB的AUROCs)和發(fā)現(xiàn)T細(xì)胞炎癥的GEP評分的- 0.318截止點(diǎn)(通過分析泛癌數(shù)據(jù)選擇)(15)。

  Rates of response to pembrolizumab were greater in patients with TMBhi (greater than or equal to Youden Index cut points)than in those with low TMB (TMBlo) (less than Youden Index cut points) and were similarly greater for those with higher T cell–inflamed GEP scores (greater than or equal to the cutoff of ?0.318) than for those with lower scores (less than the ?0.318 cutoff) (Fig. 2B).

  TMBhi患者(大于或等于Youden指數(shù)減少點(diǎn))pembrolizumab反應(yīng)率要大于那些(TMBlo)低的(少于Youden指數(shù)減少點(diǎn)),同樣大的得分更高的T cell-inflamed GEP(大于或等于截止?0.318)大于那些成績差的(小于?0.318截止)(圖2 b)于置。

  The highest objective response rate was observed for patients within each cohort who had both TMBhi and GEPhi.

  在每個(gè)隊(duì)列中茧吊，同時(shí)患有TMBhi和GEPhi的患者的客觀反應(yīng)率最高。

  Additionally, among patients with both TMBlo andlowTcell–inflamed GEP scores(GEPlo),no responses were observed in the pan-tumor and HNSCC cohorts and only one response was observed in the melanoma cohort, suggesting greater sensitivity for the combination of biomarkers.

  此外八毯，在TMB低和低細(xì)胞炎癥性GEP評分(GEPlo)患者中搓侄，泛腫瘤組和HNSCC組均未觀察到反應(yīng)，而黑色素瘤組僅觀察到一種反應(yīng)话速，這表明對生物標(biāo)志物組合的敏感性更高讶踪。

  Patients who had high scores for only one of the biomarkers (TMBlo GEPhi and TMBhi GEPlo) had moderate responses (Fig. 2B).

  只有一種生物標(biāo)志物(TMBlo GEPhi和TMBhi GEPlo)得分較高的患者反應(yīng)中等(圖2B)。

  These data suggest the potential for greater positive and negative predictive value when these biomarkers are used together in the setting of PD-1– directed monotherapy

  這些數(shù)據(jù)表明泊交，當(dāng)這些生物標(biāo)志物同時(shí)用于PD-1定向單藥治療時(shí)乳讥，可能具有更大的陽性和陰性預(yù)測值
  

  fig2B

Patient stratification by TMB and GEP was also differentially associated with PFS.

患者TMB和GEP分層與PFS也有差異柱查。

In all three cohorts, hazard ratios associated with PFS were<1.0(implyingPFSbenefit)among patients with high versus low TMB and high versus low Tcell–inflamed GEP scores.

在所有三個(gè)隊(duì)列中，與PFS相關(guān)的危險(xiǎn)比在TMB高與低云石、tcell炎癥的GEP評分高與低的患者中均<1.0(暗pfsbenefit)唉工。

The most pronounced PFS-associated hazardratios were observed for TMBhi GEPhi tumors in the pan-tumor (Fig. 3A), HNSCC (Fig. 3B), and melanoma cohorts (Fig. 3C).

在泛腫瘤(圖3A)、HNSCC(圖3B)和黑色素瘤(圖3C)中汹忠，最顯著的與pfs相關(guān)的hazardratios被觀察到用于TMBhi GEPhi腫瘤淋硝。

fig3AB

fig3C

The greatest differential was observed in eachcohortforpatientswithTMBhi GEPhi versus patients with TMBlo GEPlo.

最大的差異出現(xiàn)在患有tmbhi GEPhi的患者與患有TMBlo GEPlo的患者之間。

Patients who had greater levels of either TMB or GEP (TMBhi or GEPhi) versus low levels of these biomarkers (TMBlo or GEPlo) also had longer PFS

TMB或GEP (TMBhi或GEPhi)水平較高的患者與這些生物標(biāo)志物(TMBlo或GEPlo)水平較低的患者相比宽菜，PFS也較長谣膳。

We also explored the feasibility and potential clinical value of identifying a pan-cancer threshold for TMB across our cohorts that maximizes its joint predictive utility with GEP by using a method similar to that of Panda et al.(20).

我們還通過與Panda等人(20)類似的方法，探索了在我們的研究群體中確定TMB的泛癌閾值的可行性和潛在的臨床價(jià)值赋焕，該閾值可以最大化其與GEP的聯(lián)合預(yù)測效用参歹。

A TMB cutoff of ≥123 mutations per exome maximized the effect size of the difference in GEP distributions between tumors having TMB less than and greater than the cutoff.

每個(gè)外顯子突變數(shù)≥123的TMB截?cái)嗍鼓[瘤中TMB小于或大于截?cái)嘀档腉EP分布差異的效應(yīng)大小最大化。

The response rates to pembrolizumab in theTMB-GEP–defined groups of each clinical cohort were comparable tothoseobservedbyusingthecohort-specificcut points for TMB reported above (fig. S3).

在每個(gè)臨床隊(duì)列的TMB- gep定義的組中隆判，pembrolizumab的應(yīng)答率與使用上述TMB的特定切點(diǎn)觀察到的應(yīng)答率相當(dāng)(圖S3)犬庇。

The hazard ratios observed for PFS were also generally similar with the use of the TMB cutoff of ≥123mutations per exome(fig.S4).

使用每個(gè)外顯子組≥123個(gè)突變的TMB截止值，觀察到PFS的危險(xiǎn)比也大致相似(圖s4)侨嘀。

Apan-tumor threshold may be further optimized with the availability of additional data beyond those in ourstudy.

在我們的研究之外臭挽，隨著更多數(shù)據(jù)的可用性，pan-tumor閾值可能會(huì)進(jìn)一步優(yōu)化咬腕。

For example,apan-tumorTMB threshold of ≥175 mutations per exome was recently reported for response to pembrolizumab (21).

例如欢峰，最近報(bào)道了每個(gè)外顯子組≥175個(gè)突變的apan-tumorTMB閾值對pembrolizumab的應(yīng)答(21)。

** (TMB,TME,預(yù)測反應(yīng)應(yīng)答涨共，用PFC,BOR評估纽帖，分腫瘤類型)**

Association of other DNA-based measures with response

其他基于dna的措施與反應(yīng)的關(guān)聯(lián)

• The predictive value of other DNA-based measuresofmutationstatusinrelationtoresponse was also evaluated in these cohorts, including predicted neoantigen signature, smoking status, APOBEC-driven mutations, UV light exposure, DNA transversions, homologous recombination deficiency, and MSI.

  其他基于DNA的突變狀態(tài)與反應(yīng)無關(guān)的預(yù)測價(jià)值也在這些隊(duì)列中進(jìn)行了評估，包括預(yù)測的新抗原特征举反、吸煙狀況懊直、中風(fēng)導(dǎo)致的突變、紫外線照射火鼻、DNA轉(zhuǎn)位室囊、同源重組缺陷和MSI。

  Aside from MSI, none of thesespecificmeasuresof geneticalterationprovided additional meaningful improvement in predictive value over TMB assessment alone.

  除了MSI魁索，沒有任何一種特別的基因改變測量方法比TMB評估提供了額外的有意義的預(yù)測價(jià)值的改善融撞。

• The predicted neoantigen load was highly correlated with TMB in the pan-tumor, HNSCC, and melanoma cohorts (r = 0.87, 0.83, and 0.90, respectively), as expected (fig. S5).

  在泛腫瘤組、HNSCC組和黑色素瘤組中粗蔚，預(yù)測的新抗原載量與TMB高度相關(guān)(r分別為0.87尝偎、0.83和0.90)，與預(yù)期一致(圖S5)鹏控。

  In the pan-tumor cohort, most measures of mutagenic processes were significantly associated with BOR (e.g., predicted neoantigen load and smoking;both P values = 0.001), with similar relevant trends toward significant association with PFS (table S4).

  在泛腫瘤隊(duì)列中致扯，大多數(shù)誘變過程的測量與BOR顯著相關(guān)(例如趁窃，預(yù)測新抗原載量和吸煙;兩個(gè)P值均= 0.001)，與PFS顯著相關(guān)的趨勢相似(表S4)急前。

  By using a WES-based method to infer MSI (22), two patients with MSI-H tumors (gastric and biliary tractcarcinomas) wereidentified,and both were responders;the MSI status of these patients was confirmed with standard MSI polymerase chain reaction (PCR) methods.

  采用基于wesbased的方法推斷MSI(22)醒陆，識(shí)別出2例MSI- h腫瘤(胃和膽道氣管癌)患者，均為應(yīng)答者;采用標(biāo)準(zhǔn)MSI聚合酶鏈反應(yīng)(PCR)方法檢測患者的MSI狀態(tài)裆针。

  In the melanoma cohort, the percentage of UV light– inducedmutationscorrelatedwithTMB(r=0.77;P < 1 × 10 ?10) (fig. S1) and was significantly associated with response (P = 0.02).

  在黑色素瘤隊(duì)列中刨摩，紫外線誘導(dǎo)突變的百分比與tmb相關(guān)(r=0.77;P < 1×10?10)(圖S1)，與反應(yīng)顯著相關(guān)(P = 0.02)世吨。

  These data suggest that nonsynonymous mutations arising from a wide variety of mutagenic processes are capable of enhancing the antigenicity of tumors, withcomparableeffects ontheresponse to PD1 checkpoint blockade.

  這些數(shù)據(jù)表明澡刹，由多種誘變過程引起的非同義突變能夠增強(qiáng)腫瘤的抗原性，而對PD1檢查點(diǎn)阻斷的反應(yīng)則具有可比性耘婚。

Somatic mutation clonality and copy number variation (CNV) have previously been reported topositivelyandnegativelyassociate,respectively, with response to PD-1 checkpoint blockade (23, 24).

體細(xì)胞突變克隆性(Somatic mutation clonality)和拷貝數(shù)變異(copy number variation, CNV)分別與PD-1檢查點(diǎn)阻斷反應(yīng)相關(guān)(23,24)罢浇。

Inananalysisofclonalversusnonclonal tumors (clonality of 1 versus <1, respectively), the treatmentresponserateswerenumericallyhigher in clonal tumors in the pan-tumor cohort (18% versus10%)butnotdifferentintheHNSCC(21% versus 23%) or melanoma (44% versus 41%) cohort.

克隆性與非克隆性腫瘤(克隆性分別為1與<1)的分析顯示，在泛腫瘤隊(duì)列中克隆性腫瘤的治療反應(yīng)率(18%比10%)要高沐祷，但在hnscc(21%比23%)或黑色素瘤(44%比41%)隊(duì)列中沒有差異嚷闭。

A low and nonsignificant overall correlation was observed between clonality and TMB (r = 0.05;P>0.05)inthepooleddataset,suggestinga potentialutilityofincluding clonality assessment in the application of a TMB-based biomarker.

在匯集的數(shù)據(jù)集中，克隆性與TMB之間存在較低且不顯著的總體相關(guān)性(r = 0.05;P>0.05)赖临，這表明在基于TMB的生物標(biāo)志物的應(yīng)用中胞锰，克隆性評估具有潛在價(jià)值。

Higher levels of CNV trended toward negative associations with response but approached statisticalsignificanceonlyintheHNSCCandmelanoma cohorts (AUROCs = 0.48, 0.35, and 0.42;P=notsignificant,0.1,and0.1forthepan-tumor, HSNCC, and melanoma cohorts, respectively).

CNV水平越高兢榨，與反應(yīng)呈負(fù)相關(guān)嗅榕，但只有在高黑素瘤組才有統(tǒng)計(jì)學(xué)意義(AUROCs = 0.48、0.35和0.42;在泛腫瘤組吵聪、HSNCC組和黑色素瘤組中凌那，P=不顯著，分別為0.1和0.1)吟逝。

Correlations between TMB and CNV load were low in the pan-tumor (r = ?0.03), HNSCC (r = 0.16),andmelanoma(r=?0.12)cohorts(P>0.05 for all), suggesting a potential complementary role of CNV in biomarker-based prediction of responders versus nonresponders

泛腫瘤組(r= - 0.03)帽蝶、HNSCC組(r= 0.16)和黑色素瘤組(r= - 0.12)中，TMB和CNV負(fù)荷之間的相關(guān)性較低(P>0.05)澎办，這表明CNV在基于生物標(biāo)志物的預(yù)測應(yīng)答者和無應(yīng)答者中具有潛在的互補(bǔ)作用

（其它與抗原反應(yīng)相關(guān)研究）

TMB and Tcell–inflamed GEP relationships can be applied to a wide range of tumor types across genomic databases

TMB和t cell炎癥的GEP關(guān)系可以應(yīng)用于基因組數(shù)據(jù)庫的多種腫瘤類型

To explore the generalizability of our findings and the utility of our stratification schema across tumor types,the relationship among TMB, T cell –inflamed GEP, and related genomic features was further explored in TCGA (n = 9963 patients with transcriptomic data,6384 of which also had WES data) (16).

探索我們的研究結(jié)果的普遍性和實(shí)用的分層模式在腫瘤類型,在TMB,T細(xì)胞發(fā)炎GEP和相關(guān)基因功能進(jìn)一步探索TCGA (n = 9963患者轉(zhuǎn)錄組數(shù)據(jù),其中6384也有WES數(shù)據(jù))(16)嘲碱。

Patients were stratified by TMB (WES score ≤ 100 mutations per exome) and T cell–inflamed GEP score (below the top tertile of data) by using cutoffs equivalent in terms of prevalence to those that were used to define the clinical response groups in the pan tumor cohort (Fig. 4A).

患者按TMB(每個(gè)外顯子組的WES評分≤100個(gè)突變)和T細(xì)胞炎癥性GEP評分(數(shù)據(jù)頂部三分位以下)進(jìn)行分層金砍，使用與定義泛腫瘤隊(duì)列中臨床反應(yīng)組的患病率相同的截?cái)嘀?圖4A)局蚀。

fig4A

Consistent with our clinical data, TMB and the T cell–inflamed GEP were found to have low but significant correlations(r=0.30;P <1×10 ?4),as did TMB and PDL1 gene expression (r = 0.16;P < 1 × 10 ?4) and TMB and PD-L2 gene expression (r = 0.22;P < 1×10 - 4)。

與我們的臨床數(shù)據(jù)一致恕稠，TMB與T細(xì)胞炎癥性GEP呈低而顯著的相關(guān)性(r=0.30;P <1×10?4)琅绅，TMB與PDL1基因表達(dá)(r= 0.16;P <1×10?4)，TMB與PD-L2基因表達(dá)(r= 0.22;P < 1×10 ?4).

By contrast,both PD-L1 expression and PD-L2 expression, which are induced by IFN-g from activated Th1 and cytotoxic T cells (1–3), were highly correlated with the T cell–inflamed GEP (r = 0.61 and 0.72;P < 1 × 10 ?10).

而活化Th1和細(xì)胞毒T細(xì)胞IFN-g誘導(dǎo)的PD-L1和PD-L2表達(dá)與T細(xì)胞炎癥性GEP高度相關(guān)(r = 0.61和0.72;P < 1×10?10)鹅巍。

MSI-H tumors made up a subset of tumors with TMBhi inbothTcell–inflamedandnoninflamedtumors.

MSI-H腫瘤是TMBhi合并細(xì)胞炎性和非炎性腫瘤的一個(gè)亞型千扶。

Even in these tumors, which exhibit very high mutational burdens, the modest correlation between GEP and TMB was preserved.

即使在這些表現(xiàn)出非常高的突變負(fù)擔(dān)的腫瘤中料祠，GEP和TMB之間的適度相關(guān)性也得到了保留。

The frequency of the TMBhi GEPhi subgroup, which was identified as the most clinically responsive population in our datasets, varied across cancer types (Fig. 4B), with enrichment among patients with tumors that are generally more responsive to pembrolizumab, such as melanoma and NSCLC (25, 26), and underrepresentation among patients with tumors such as prostate cancer and glioblastoma that are typically more resistant to immunotherapy (27, 28).

TMBhi GEPhi子群的頻率,在我們的數(shù)據(jù)集被確認(rèn)為臨床上最敏感反應(yīng)的人口,不同癌癥類型不同(圖4 b),在腫瘤患者通常反應(yīng)pembrolizumab更加多,如黑色素瘤和非小細(xì)胞肺癌(25澎羞、26)和前列腺癌等腫瘤患者中髓绽，在膠質(zhì)母細(xì)胞瘤代表名額不足,但通常抗免疫療法(27妆绞，28)顺呕。

fig4B

Rooted in the well-studied field of T cell inflammation and cytolytic process (13, 29–31), the T cell–inflamed GEP signature was derived by a stepwise process of discovery, validation, and refinement of candidate gene sets associated with patient response to pembrolizumab across multiple solid tumors with the use of a NanoString platform enriched in immune genes (15) and thus represents a universal signature.

根植于T細(xì)胞炎癥和細(xì)胞溶解的過程的研究領(lǐng)域(13 29-31),T cell-inflamed GEP代表特征是派生的一個(gè)逐步的過程發(fā)現(xiàn),驗(yàn)證和改進(jìn)相關(guān)的候選基因集跨多個(gè)實(shí)體腫瘤病人應(yīng)對pembrolizumab NanoString平臺(tái)使用富含免疫基因(15),因此代表了一種普遍的代表。

Notably, in TCGA dataset, we observed a strong correlation (r > 0.9) between the GEP and several other previously published transcriptional signatures reflective of a T cell–inflamed TME associated with cytolytic processes (Fig. 5A).

值得注意的是括饶，在TCGA數(shù)據(jù)集中株茶，我們觀察到GEP和其他幾個(gè)先前發(fā)表的反映T細(xì)胞炎癥性TME與細(xì)胞溶解過程相關(guān)的轉(zhuǎn)錄特征之間有很強(qiáng)的相關(guān)性(r > 0.9)(圖5A)。

（公共數(shù)據(jù)中驗(yàn)證相光關(guān)系）

fig5A