{"doi":"10.1101/2023.12.24.573257","title":"Cytotoxic chemotherapy potentiates the immune response and efficacy of combination CXCR4/PD-1 inhibition in models of pancreatic ductal adenocarcinoma","abstract":"Purpose: The CXCL12-CXCR4 chemokine axis plays a significant role in modulating T-cell infiltration into the pancreatic tumor microenvironment. Despite promising preclinical findings, clinical trials combining inhibitors of CXCR4 (AMD3100/BL-8040) and anti-programmed death 1/ligand1 (anti-PD1/PD-L1) have failed to improve outcomes. Experimental Design: We utilized a novel ex vivo autologous patient-derived immune/organoid (PDIO) co-culture system using human peripheral blood mononuclear cells and patient derived tumor organoids, and in vivo the autochthonous LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) pancreatic cancer mouse model to interrogate the effects of either monotherapy or all combinations of gemcitabine, AMD3100, and anit-PD1 on CD8+ T cell activation and survival. Results: We demonstrate that disruption of the CXCL12-CXCR4 axis using AMD3100 leads to increased migration and activation of CD8+ T-cells. In addition, when combined with the cytotoxic chemotherapy gemcitabine, CXCR4 inhibition further potentiated CD8+ T-cell activation. We next tested the combination of gemcitabine, CXCR4 inhibition, and anti-PD1 in the KPC pancreatic cancer mouse model and demonstrate that this combination markedly impacted the tumor immune microenvironment by increasing infiltration of natural killer cells, the ratio of CD8+ to regulatory T-cells, and tumor cell death while decreasing tumor cell proliferation. Moreover, this combination extended survival in KPC mice. Conclusions: These findings suggest that combining gemcitabine with CXCR4 inhibiting agents and anti-PD1 therapy controls tumor growth by reducing immunosuppression and potentiating immune cell activation and therefore may represent a novel approach to treating pancreatic cancer.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":393969,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1168759,"name":"Ilenia Pellicciotta","orcid":null,"position":1,"is_corresponding":false},{"id":106337,"name":"Carmine F. Palermo","orcid":"0009-0004-6790-5493","position":2,"is_corresponding":false},{"id":1168760,"name":"Steven A. Sastra","orcid":null,"position":3,"is_corresponding":false},{"id":484906,"name":"Andrew Chen","orcid":"0000-0001-5303-3285","position":4,"is_corresponding":false},{"id":1168761,"name":"Emily Alouani","orcid":null,"position":5,"is_corresponding":false},{"id":106328,"name":"H. Carlo Maurer","orcid":"0000-0002-2193-6014","position":6,"is_corresponding":false},{"id":626325,"name":"Michael May","orcid":"0000-0002-6187-4655","position":7,"is_corresponding":false},{"id":106349,"name":"Alina C. Iuga","orcid":"0000-0002-2351-8289","position":8,"is_corresponding":false},{"id":261872,"name":"Raúl Rabadán","orcid":"0000-0001-7946-9255","position":9,"is_corresponding":false},{"id":106352,"name":"Kenneth P. Olive","orcid":"0000-0002-3392-8994","position":10,"is_corresponding":false},{"id":322445,"name":"Gulam A. Manji","orcid":"0000-0001-9817-2414","position":11,"is_corresponding":false},{"id":728272,"name":"Alexander G. Raufi","orcid":"0000-0001-5645-2629","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T01:19:10.334330Z","pmid":"38234792","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}