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557 Chronicity of exposure and ensuing resistance to platinum chemotherapy sensitizes homologous recombination-deficient pancreatic ductal adenocarcinoma to immune checkpoint blockade
  1. Ifeanyichukwu Ogobuiro,
  2. Anna Bianchi,
  3. Lucas Caeiro,
  4. Haleh Amirian,
  5. Luis Alberto Nivelo,
  6. Iago De Castro Silva,
  7. Karthik Rajkumar,
  8. Andrew Adams,
  9. Vanessa Garrido,
  10. Samara Singh,
  11. Nagaraj Nagathihalli,
  12. Nipun Merchant and
  13. Jashodeep Datta
  1. University of Miami Miller School of Medicine, Miami, FL, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Although platinum-based chemotherapy is standard treatment for pancreatic ductal adenocarcinoma (PDAC) patients with either germline/somatic deficiencies in homologous recombination (mutHRD), a subset become platinum-resistant. We have shown that patients with mutHRD PDAC progressing on platinum chemotherapy respond to ICB. We sought to model these clinical findings in preclinical models to interrogate mechanisms that drive immune checkpoint blockade (ICB) sensitivity.

Methods mutHRD PDAC patients who received treatment with anti-PD-1+anti-CTLA4 ICB following resistance to platinum-based chemotherapy were selected. Cisplatin-sensitive and resistant Brca2-silenced (via shRNA knockdown) KPC cancer cells were generated and characterized in-vitro and in-vivo.

Results In 12 mutHRD PDAC patients treated with ICB after progression on platinum-based chemotherapy, duration of platinum exposure was associated with post-ICB disease response. Tumor-bearing syngeneic mice implanted with cisplatin-sensitive or resistant shBrca2 or wildtype KPC tumor cells treated with standard-of-care gemcitabine+cisplatin chemotherapy demonstrated expected rapid tumor growth of cisplatin-resistant shBrca2 tumors. However, we observed a profound reduction in tumor volumes of these chronically cisplatin-resistant KPC-shBrca2 tumors when subsequently treated with anti-PD-1+anti-CTLA4 ICB compared to wildtype-KPC or cisplatin-sensitive KPC-shBrca2 tumors. To understand mechanistic underpinnings of these novel observation, whole transcriptome sequencing revealed significant differential upregulation of type-1 interferon and cGAS-STING pathways in cisplatin-resistant KPC-shBrca2 compared to wildtype-KPC or cisplatin-sensitive KPC-shBrca2 controls. These transcriptomic changes manifested in a secretome enriched for T-cell trafficking cytokines CXCL10, CXCL9, and CCL5 from cisplatin-resistant KPC-shBrca2 cells. Indeed, cisplatin-resistant KPC-shBrca2 cells promoted increased transwell T-cell trafficking in-vitro as well as increased CD8+ T-cell infiltration in subcutaneous tumors in-vivo, compared with controls.

Conclusions Chronicity of platinum exposure in mutHRD PDAC potentiates ICB sensitivity via induction of cell-autonomous type-1 interferon/cGAS-STING signaling and ensuing T-cell trafficking to the tumor microenvironment.

Acknowledgements I. Ogobuiro was supported by NIH/NCI T32 (to N. Merchant). This work was supported by KL2 career development grant by the Miami Clinical and Translational Science Institute (CTSI) under NIH Award UL1TR002736, American College of Surgeons Franklin H. Martin Research Fellowship, Association for Academic Surgery Joel J. Roslyn Faculty Award, Society of Surgical Oncology Young Investigator Award, and Elsa U. Pardee Foundation Award (to J. Datta). Research reported in this publication was supported by the NCI/NIH Award P30CA240139 to the Sylvester Comprehensive Cancer Center.

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