Multimodality analysis confers a prognostic benefit of a T-cell infiltrated tumor microenvironment and peripheral immune status in patients with melanoma.
Multimodality analysis confers a prognostic benefit of a T-cell infiltrated tumor microenvironment and peripheral immune status in patients with melanoma.
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DOI：
10.1136/jitc-2022-005052
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发表时间：
2022-09
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
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作者：
我们之前报道了一项 1 期研究的结果，该研究在 12 名黑色素瘤患者中测试了瘤内重组脊髓灰质炎病毒 Lerapolturev。所有12名患者在lerapolturev治疗前均接受了抗PD-1全身治疗，这12名患者中有11名在lerapolturev治疗后也接受了抗PD-1治疗。在临床前模型中，lerapolturev 会诱导肿瘤内先天性炎症，从而与抗肿瘤 T 细胞发生作用。在当前的研究中，评估了 prelerapolturev 和 postlerapolturev 肿瘤活检和血液的反应生物标志物。对肿瘤组织 (n=11) 进行了以下分析：(1) 免疫细胞密度的流式细胞术评估，(2) 蛋白质和转录组的 NanoString 数字空间分析，以及 (3) 批量 RNA 测序。在外周血中测量免疫细胞表型和对体外刺激（包括体外 lerapolturev 攻击）的反应性（n=12）。 lerapolturev 治疗 30 天内接受抗 PD-1 治疗的 3 名患者目前的中位无进展生存期 (PFS) 为 2.3 年，并且在 prelerapolturev 肿瘤活检中具有较高的 CD8+T 细胞浸润，而 7 名患者的中位 PFS 为 1.6 个月且在 prelerapolturev 肿瘤活检中具有较低的 CD8+T 细胞浸润。在外周血中，与中位 PFS 为 1.6 个月的 8 名患者相比，4 名 PFS 为 2.3 年的患者（包括 3 名在 lerapolturev 治疗前 30 天内接受过抗 PD-1 治疗且治疗前肿瘤 CD8+T 细胞浸润较高的患者）具有显着较高的效应记忆（CD8+、CCR7-、CD45RA-），但 CD8+PD-1+ 和 CD4+PD-1+ 细胞较低。此外，与中位 PFS 为 1.6 个月的 8 名患者相比，四名中位 PFS 为 2.3 年的患者的治疗前血液对体外 lerapolturev 攻击具有更强的抗病毒反应。在一小群患者中，可能由先前的抗 PD-1 治疗和对 lerapolturev 的熟练外周血预处理先天免疫反应（抗病毒/干扰素信号传导）引起的治疗前肿瘤微环境发炎，与肿瘤内 lerapolturev 后的长期 PFS 相关。这些发现暗示瘤内 T 细胞炎症与外周免疫功能之间存在联系。 NCT03712358。
We previously reported results from a phase 1 study testing intratumoral recombinant poliovirus, lerapolturev, in 12 melanoma patients. All 12 patients received anti-PD-1 systemic therapy before lerapolturev, and 11 of these 12 patients also received anti-PD-1 after lerapolturev. In preclinical models lerapolturev induces intratumoral innate inflammation that engages antitumor T cells. In the current study, prelerapolturev and postlerapolturev tumor biopsies and blood were evaluated for biomarkers of response. The following analyses were performed on tumor tissue (n=11): (1) flow cytometric assessment of immune cell density, (2) NanoString Digital Spatial profiling of protein and the transcriptome, and (3) bulk RNA sequencing. Immune cell phenotypes and responsiveness to in vitro stimulation, including in vitro lerapolturev challenge, were measured in peripheral blood (n=12). Three patients who received anti-PD-1 therapy within 30 days of lerapolturev have a current median progression-free survival (PFS) of 2.3 years and had higher CD8+T cell infiltrates in prelerapolturev tumor biopsies relative to that of 7 patients with median PFS of 1.6 months and lower CD8+T cell infiltrates in prelerapolturev tumor biopsies. In peripheral blood, four patients with PFS 2.3 years (including three that received anti-PD-1 therapy within 30 days before lerapolturev and had higher pretreatment tumor CD8+T cell infiltrates) had significantly higher effector memory (CD8+, CCR7-, CD45RA-) but lower CD8+PD-1+ and CD4+PD-1+ cells compared with eight patients with median PFS 1.6 months. In addition, pretreatment blood from the four patients with median PFS 2.3 years had more potent antiviral responses to in vitro lerapolturev challenge compared with eight patients with median PFS 1.6 months. An inflamed pretreatment tumor microenvironment, possibly induced by prior anti-PD-1 therapy and a proficient peripheral blood pretreatment innate immune response (antiviral/interferon signaling) to lerapolturev was associated with long term PFS after intratumoral lerapolturev in a small cohort of patients. These findings imply a link between intratumoral T cell inflammation and peripheral immune function. NCT03712358.
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影响因子：
17.1
作者：
Brown MC;Holl EK;Boczkowski D;Dobrikova E;Mosaheb M;Chandramohan V;Bigner DD;Gromeier M;Nair SK
通讯作者：
Nair SK
影响因子：
11.5
作者：
Kim, Kyung Hwan;Cho, Jinhyun;Shin, Eui-Cheol
通讯作者：
Shin, Eui-Cheol
影响因子：
64.8
作者：
Delorey TM;Ziegler CGK;Heimberg G;Normand R;Yang Y;Segerstolpe Å;Abbondanza D;Fleming SJ;Subramanian A;Montoro DT;Jagadeesh KA;Dey KK;Sen P;Slyper M;Pita-Juárez YH;Phillips D;Biermann J;Bloom-Ackermann Z;Barkas N;Ganna A;Gomez J;Melms JC;Katsyv I;Normandin E;Naderi P;Popov YV;Raju SS;Niezen S;Tsai LT;Siddle KJ;Sud M;Tran VM;Vellarikkal SK;Wang Y;Amir-Zilberstein L;Atri DS;Beechem J;Brook OR;Chen J;Divakar P;Dorceus P;Engreitz JM;Essene A;Fitzgerald DM;Fropf R;Gazal S;Gould J;Grzyb J;Harvey T;Hecht J;Hether T;Jané-Valbuena J;Leney-Greene M;Ma H;McCabe C;McLoughlin DE;Miller EM;Muus C;Niemi M;Padera R;Pan L;Pant D;Pe'er C;Pfiffner-Borges J;Pinto CJ;Plaisted J;Reeves J;Ross M;Rudy M;Rueckert EH;Siciliano M;Sturm A;Todres E;Waghray A;Warren S;Zhang S;Zollinger DR;Cosimi L;Gupta RM;Hacohen N;Hibshoosh H;Hide W;Price AL;Rajagopal J;Tata PR;Riedel S;Szabo G;Tickle TL;Ellinor PT;Hung D;Sabeti PC;Novak R;Rogers R;Ingber DE;Jiang ZG;Juric D;Babadi M;Farhi SL;Izar B;Stone JR;Vlachos IS;Solomon IH;Ashenberg O;Porter CBM;Li B;Shalek AK;Villani AC;Rozenblatt-Rosen O;Regev A
通讯作者：
Regev A
影响因子：
--
作者：
Gajewski TF;Corrales L;Williams J;Horton B;Sivan A;Spranger S
通讯作者：
Spranger S
影响因子：
16.6
作者：
Brown MC;Mosaheb MM;Mohme M;McKay ZP;Holl EK;Kastan JP;Yang Y;Beasley GM;Hwang ES;Ashley DM;Bigner DD;Nair SK;Gromeier M
通讯作者：
Gromeier M