Cytotoxic chemotherapy potentiates the immune response and efficacy of combination CXCR4/PD-1 inhibition in models of pancreatic ductal adenocarcinoma

Raufi, A. G.; Pellicciotta, I.; Palermo, C.; Sastra, S.; Chen, A.; Alouani, E.; Maurer, C.; May, M.; Iuga, A.; Rabadan, R.; Olive, K. P.; Manji, G. A.

doi:10.1101/2023.12.24.573257

bioRxiv · 10.1101/2023.12.24.573257

Cytotoxic chemotherapy potentiates the immune response and efficacy of combination CXCR4/PD-1 inhibition in models of pancreatic ductal adenocarcinoma

Raufi, A. G.·Pellicciotta, I.·Palermo, C.·Sastra, S.·Chen, A.·Alouani, E.·Maurer, C.·May, M.·Iuga, A.·Rabadan, R.·Olive, K. P.·Manji, G. A.

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Abstract

PurposeThe 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 DesignWe 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. ResultsWe 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. ConclusionsThese 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.

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Raufi, A. G., Pellicciotta, I., Palermo, C., Sastra, S., Chen, A., Alouani, E., Maurer, C., May, M., Iuga, A., Rabadan, R., Olive, K. P., Manji, G. A.. 2023-12-25. Cytotoxic chemotherapy potentiates the immune response and efficacy of combination CXCR4/PD-1 inhibition in models of pancreatic ductal adenocarcinoma. https://doi.org/10.1101/2023.12.24.573257

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