PO.CL05.06 · 临床研究
Cytotoxic T-cell signatures underlie therapeutic response to 177Lu-DOTATATE plus pembrolizumab in well-differentiated gastroenteric neuroendocrine tumors
作者与单位
摘要 Abstract
Background
Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE is an established treatment for well-differentiated neuroendocrine tumors (WD-NETs). PD-1 blockade with pembrolizumab has been investigated in NETs; however, radiographic responses are limited when used as monotherapy. As such, we investigated the combination of PRRT and pembrolizumab as an investigational approach to enhance antitumor immunity and efficacy in 26 patients with grade 2 or 3 WD-NET (NCT03457948). The overall response rate (ORR) by RECIST 1.1 was 34.6% (9/26), but the systemic immune changes induced by this combination remain incompletely understood. We now report the results of our investigation of peripheral immune remodeling and T-cell clonal dynamics using single-cell (sc) transcriptomic and TCR repertoire profiling of PBMCs.
Methods
A total of 111 PBMC samples were collected longitudinally from 26 patients treated with PRRT plus pembrolizumab. scRNA sequencing and TCR sequencing were performed using the 10x Genomics platform. Major immune populations were annotated, and transcriptional and clonal characteristics were analyzed in relation to treatment response. Patients were stratified into pancreatic NET (pNET, N=14; 5 responders [36%, PR] and 9 non-responders [64%; 7 SD, 2 PD]) and extrapancreatic NET (epNET, N=12; 4 responders [33%, PR] and 8 non-responders [67%; 7 SD, 1 PD]), with the latter including tumors of intestinal, pulmonary, and unknown primary origin. Statistical analysis was performed with Mann-Whitney U test.
Results
In epNET responders, the frequency of CD8⁺ T cells increased across timepoints compared with epNET non-responders (p<0.05). Further subclustering of T cells revealed that both CD4⁺ and a subset of CD8⁺ cytotoxic T cells were significantly elevated (p<0.05) and exhibited prominent clonal expansion in epNET responders, particularly post treatment. Non-responders showed an enrichment of immunosuppressive subsets, including CD4⁺ regulatory T cells (Treg) and CD4⁺
Th2 cells (p<0.05). Differential gene expression analysis demonstrated that several cytotoxic genes ( N KG7 , CCL5 , GNLY , and GZMH ) were upregulated in both CD4⁺ and CD8⁺ T cells in the responders compared with non-responders. In contrast to epNET, systemic immune remodeling was generally limited in pNET patients regardless of response status.
Conclusions
Integrated single-cell and TCR analysis revealed distinct systemic T-cell activation profiles between responders and non-responders to PRRT plus PD-1 blockade, but this effect varied by site of origin. Responding patients with epNET exhibited prominent clonal expansion and upregulation of cytotoxic genes. These findings highlight key differences in peripheral immune dynamics associated with treatment response in WD-NETs and may inform strategies to optimize combination therapy.
利益披露 Disclosure
N. Mizutani,
Daiichi Sankyo Co., Lts Employment.
S. Shukla, None.
N. Fidelman,
Merck & Co., Inc. ).
B. P. Keenan,
AstraZeneca ).
Roche/Genentech ).
Regeneron ).
Takeda ).
Antengene ).
Innovative Cellular Therapeutics ).
Affini-T ).
Pyxis Oncology ).
Arcellx Independent Contractor.
Agenus Inc. Independent Contractor.
Cartography Biosciences Independent Contractor.
Roche/Genentech Travel.
D. Y. Oh,
Merck ).
PACT Pharma ).
the Parker Institute for Cancer Immunotherapy ).
Poseida Therapeutics ).
TCR2 Therapeutics ).
Roche/Genentech ).
Nutcracker Therapeutics ).
Amgen ).
Allogene Therapeutics ).
Roche/Genentech Travel.
Poseida Therapeutics Travel.
DAVA Oncology Travel.
Tatum Bioscience g., Board of Directors, non-salaried role).
Cartography Biosciences g., Board of Directors, non-salaried role).
Revelation Partners Independent Contractor.
K. Chan, None.
L. Zhang,
Motive Medical Intelligence Independent Contractor.
Smith-Kettlewell Eye Research Institute Independent Contractor.
Serna Bio Independent Contractor.
E. K. Bergsland,
Merck & Co., Inc. ).
T. Hope,
Bayer ).
GE Healthcare ).
Lantheus ).
Janssen ).
Novartis ).
Telix Pharmaceuticals ).
the Prostate Cancer Foundation ).
National Cancer Institute ).
AstraZeneca Independent Contractor.
Bayer Independent Contractor.
Cardinal Health Independent Contractor.
BlueEarth Diagnostics Independent Contractor.
Lantheus Independent Contractor.
Molecular Partners Independent Contractor.
Novartis Independent Contractor.
RayzeBio/BMS Independent Contractor.
Sanofi Independent Contractor.
Curium Stock.
AdvanCell Stock.
Utter Therapeutics Stock.
L. Fong,
Merck & Co., Inc. g., Board of Directors, non-salaried role), ).
Roche/Genentech g., Board of Directors, non-salaried role), ).
Actym g., Board of Directors, non-salaried role).
Astra Zeneca g., Board of Directors, non-salaried role).
Bioatla g., Board of Directors, non-salaried role).
Boehringer Ingelheim g., Board of Directors, non-salaried role).
Daiichi Sankyo g., Board of Directors, non-salaried role).
Immunogenesis g., Board of Directors, non-salaried role).
Innovent g., Board of Directors, non-salaried role).
Merck KGA g., Board of Directors, non-salaried role).
Nutcracker g., Board of Directors, non-salaried role).
Sutro g., Board of Directors, non-salaried role).