CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma

By C. Steele, S. Karim, Joshua Leach, Simon T Barry, Owen J Sansom, Jennifer P Morton Correspondence, Peter Bailey, R. Upstill-Goddard, Loveena Rishi, M. Foth and 17 more. Cancer Cell, 2016

766 citations recorded by the source corpus.

Summary CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that CXCR2 signaling is upregulated in human pancreatic cancer, predominantly in neutrophil/myeloid-derived suppressor cells, but rarely in tumor cells. Genetic ablation or inhibition of CXCR2 abrogated metastasis, but only inhibition slowed tumorigenesis. Depletion of neutrophils/myeloid-derived suppressor cells also suppressed metastasis suggesting a key role for CXCR2 in establishing and maintaining the metastatic niche. Importantly, loss or inhibition of CXCR2 improved T cell entry, and combined inhibition of CXCR2 and PD1 in mice with established disease significantly extended survival. We show that CXCR2 signaling in the myeloid compartment can promote pancreatic tumorigenesis and is required for pancreatic cancer metastasis, making it an excellent therapeutic target.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/bd7289a020845dee1dc229f49f74d8137a5eb68f

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In Immunology

1. Hugo Gonzalez
2. Zena Werb
3. C. Hagerling
4. Pengfei Lu

In Oncology

1. Hugo Gonzalez
2. Zena Werb
3. C. Hagerling
4. Pengfei Lu
5. M. Egeblad
6. Raghu Kalluri
7. Valerie M. Weaver

Citations in the corpus

• Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy (2018, neutral): “CXCR2 is required for myeloid cell infiltration into PDA (Chao et al., 2016; Wang et al., 2016; Steele et al., 2016), and we found that > 80% of gMDSCs expressed CXCR2 in both T cell high and low tumors (Figure S5J).”
• Role of the CXCL8-CXCR1/2 Axis in Cancer and Inflammatory Diseases (2017, neutral): “Combination of anti CXCR2 and other chemotherapy, particularly anti-PD1 therapy against pancreatic cancer proved more beneficial than either of single agents alone [325, 346].”
• Roles of the immune system in cancer: from tumor initiation to metastatic progression (2018, background): “This prometastatic motif is also seen during liver metastasis in the KPC model of pancreatic cancer (Steele et al. 2016).”
• Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions (2023, background): “Elimination of neutrophil infiltration leads to cancer regression and prolonged survival outcomes.(318) Sequencing of pancreatic single-cell transcriptome revealed that BHLHE40 is a key regulator of neutrophil polarization toward the TAN-1 phenotype, which has pro-cancer and immunosuppressive functi”