LBPO.CL04 · 临床研究 · Late-Breaking
Targeting XPO1 reprograms immune microenvironment and confers sensitivity to immune checkpoint blockade in pancreatic ductal adenocarcinoma
作者与单位
摘要 Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that remains largely refractory to immune checkpoint blockade, owing to a profoundly immunosuppressive and immune excluded tumor microenvironment (TME). Nuclear cytoplasmic transport is essential for immune signaling in tumor and stroma. Exportin 1 (XPO1), the dominant nuclear export receptor, is overexpressed in PDAC and has been linked to therapeutic resistance, yet its role in PDAC immunopathogenesis has not been defined.
Methods: In this study, we have utilized syngeneic and genetically engineered mouse models (GEMMs; KPC (Kras/p53/Cre)), digital spatial profiling (DSP; transcriptomics/proteomics), and single-nucleus RNA sequencing (snRNAseq). PDAC cells were treated with the selective XPO1 inhibitor Selinexor and Gemcitabine-nab-paclitaxel and profiled by bulk RNA sequencing. KPC tumors receiving Selinexor and Gemcitabine-nab-paclitaxel underwent snRNAseq, DSP, immunohistochemistry (IHC), and immune phenotyping. In Pan02 syngeneic model, Selinexor was combined with anti PD-1 antibody and tumor growth, and tumor and splenic immune subsets were quantified by flow cytometry.
Results: Treatment of PDAC with Selinexor and Gemcitabine-nab-paclitaxel induced profound immune reprogramming characterized by broad remodeling of innate and adaptive immune responses. Our transcriptomics and flow cytometry analyses revealed enrichment of immune cells with anti-tumor immune function, antigen presentation and cytotoxic T cell activation. In line with these data, snRNAseq and IHC analysis of KPC tumors demonstrated increased intratumoral CD4+ and CD8+ T cell infiltration and elevated expression of T and B cell-associated transcripts (CD3d, CD3e, CD4, CD8a, CD8b1, CD19) together with upregulation of inflammatory monocyte marker Ly6C1, indicating coordinated expansion of effector lymphoid populations and anti-tumorigenic monocytes within a dense desmoplastic stroma. Furthermore, DSP showed that Selinexor and Gemcitabine-nab-paclitaxel enhanced pathways related to MHC class II-mediated antigen processing and leukocyte activation across both tumor and stromal compartments. Selinexor and Gemcitabine-nab-paclitaxel treatment suppressed the expression of the immunosuppressive chitinase-like protein Chil3, as this was validated by IHC, western blot and qPCR suggesting attenuation of pro-tumor myeloid signaling in PDAC TME. Consistently, Selinexor combined with anti-PD-1 therapy in Pan02 models significantly reduced tumor growth without much toxicity and reprogrammed myeloid cell populations toward Ly6ChiCd11b+ phenotype.
Conclusions: Together, these data identify XPO1 driven nuclear export as a central upstream regulator of PDAC immune evasion and support clinical testing of XPO1 inhibitor immune checkpoint blockade combinations in pancreatic cancer. Ongoing validation in diverse preclinical models is informing planned clinical trials.
利益披露 Disclosure
M. Uddin, None.
M. N. Al Hallack,
Ipsen Other, Speaker.
AstraZeneca Other, Speaker.
Guardant Health Other, Speaker.
Pfizer Other, Speaker.
Takeda Other, Speaker.
M. Nagasaka,
AstraZeneca Other, Consulting or Advisory Role.
Caris Life Sciences Other, Consulting or Advisory Role.
Daiichi Sankyo Other, Consulting or Advisory Role.
Takeda Other, Consulting or Advisory Role.
Novartis Other, Consulting or Advisory Role.
EMD Serono Other, Consulting or Advisory Role.
Janssen Other, Consulting or Advisory Role.
Pfizer Other, Consulting or Advisory Role.
Lilly Other, Consulting or Advisory Role.
Genentech Other, Consulting or Advisory Role.
Mirati Therapeutics Other, Consulting or Advisory Role.
Bristol Myers Squibb USA Other, Consulting or Advisory Role.
Regeneron Other, Consulting or Advisory Role.
Blueprint Medicines Other, Speaker.
Takeda Other, Speaker.
Janssen Other, Speaker.
Mirati Therapeutics Other, Speaker.
Tempus ).
Anheart Therapeutics Jun Gong Travel.
Astellas Pharma Other, Honoraria.
S. F. Bannoura, None..
H. Y. Khan, None..
A. Aboukameel, None..
F. K. Alkan, None..
H. K. Alkan, None..
K. Choucair, None.
M. Saif,
US World Meds Other, Advisory Board.
Amal Therapeutics ).
Genentech Inc. ).
IDEAYA ).
SpringWorks Therapeutics ).
Yivia ).
HCW Biologics ).
FLASCO Other, Speaker.
Uptodate Other, Honorarium.
B. Bao, None.
I. Azar,
MJH Life Sciences Other, Honoraria.
AstraZeneca Other, Consulting or Advisory Role.
Genmab Nishant Gandhi Other, Consulting or Advisory Role.
Caris Life Sciences Employment.
E. W. Beal, None..
M. Tobon, None..
S. Kim, None..
A. Mohamed, None..
G. Dyson, None..
R. Beydoun, None..
R. M. Mohammad, None..
H. Chen, None.
B. F. El-Rayes,
Seattle Genetics ), Other, Speaker.
Exelixis Other, Advisory Board.
Beigene Other, Advisory Board.
AstraZeneca Other, Advisory Board.
Bristol-Myers Squibb ).
Merck ).
AstraZeneca ).
Boehringer Ingelheim ).
P. A. Philip,
Bayer Other, Honoraria.
Ipsen Other, Honoraria.
Incyte Other, Honoraria.
Taiho Pharmaceutical Other, Honoraria.
Astellas Pharma Other, Honoraria.
BioNTech SE Other, Honoraria.
Novocure Other, Honoraria.
TriSalus Life Sciences Other, Honoraria.
SERVIER Other, Honoraria.
Seagen Other, Honoraria.
Celgene Other, Consulting or Advisory Role.
Ipsen Other, Consulting or Advisory Role.
Merck Other, Consulting or Advisory Role.
Daiichi Sankyo Other, Consulting or Advisory Role.
SynCoreBio Other, Consulting or Advisory Role.
Novartis (Inst) ).
Regeneron (Inst) ).
Genentech (Inst) ).
Halozyme (Inst) ).
Lilly (Inst) ).
B. C. Pasche,
TheraBionic Employment, Stock, Other Business Ownership, Other, Leadership.
Merck & Co Inc ).
Roche ).
Novartis ).
AstraZeneca ).
Bristol Myers Squibb Co ).
H. Korkaya, None.
A. S. Azmi,
Gerson Lehrman Group Other, Consulting or Advisory Role.
Guidepoint Inc Other, Consulting or Advisory Role.
Purple Biotech ).
FanWave ).
Colorado chromatography ).
Blackstone Therapeutics ).