Abstract B029: Serum amyloid A proteins direct therapeutic resistance in pancreatic cancer
Authors: Lee Jesse , Stone Meredith L. , Choi Hana , Coho Heather , Beatty Gregory L. 
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a remarkable propensity for therapeutic resistance. While this resistance may reflect tumor-extrinsic factors that foster immune suppression and metastasis, the mechanisms by which these factors drive therapy resistance remain poorly understood. Here, we demonstrate that hepatocyte-directed systemic inflammation is a key determinant of therapeutic resistance in PDAC. We have previously shown that hepatocytes coordinate immune evasion in cancer via release of serum amyloid A proteins 1&2 (SAA). Tumor bearing mice lacking SAA expression (Saa− / −) demonstrate increased primary tumor infiltration of CD8+ cytotoxic T cells and improved control of primary tumor outgrowth. Thus, we hypothesized that SAA may play a role in PDAC’s profound resistance to cancer therapies. To test this, we first treated tumor bearing wild type (WT) or Saa−/− mice with either PBS control or a weekly chemotherapy regimen of gemcitabine + paclitaxel. While WT mice demonstrated little benefit from chemotherapy treatment, Saa−/− mice derived a significant overall survival benefit and improved response to chemotherapy (Log-rank p=0.01). Accordingly, we sought to understand and leverage the mechanisms by which SAA directs resistance to chemotherapy. Cytometry by time of flight (CyTOF) analysis of untreated tumors in Saa−/− mice showed an increase of anti-tumor CD80+CD86+CD206− macrophages within the tumor. Likewise, single-cell sequencing analysis revealed the accumulation of an M1-like macrophage cell population in the tumors of Saa−/− mice. Productive anti-tumor macrophage polarization can be triggered by chemotherapy-induced DNA damage and subsequent cGAS-STING pathway activation. Therefore, we hypothesized that a STING agonist could replace the chemotherapy regimen and synergize with an SAA deficiency. To test this, tumor bearing WT or Saa−/- mice were treated with a single dose of either vehicle or DMXAA, a murine STING agonist, and then followed for tumor growth and overall survival. Saa−/− mice treated with a single dose of DMXAA demonstrated a significant increase in overall survival (Log-Rank p=0.01) compared to WT mice. Moreover, we observed a significant increase of CD44+CD62L+ central memory T cells and PD-1+ T cells in the peripheral blood of Saa−/− mice after DMXAA treatment. This suggested that STING agonism in SAA deficient mice may sensitize PDAC tumors to PD-1 blockade. Indeed, treatment of PDAC tumors in Saa−/− mice with a single dose of DMXAA in combination with PD-1 blockade induced cures and significantly restrained tumor growth compared to DMXAA alone (Log-Rank p=0.04). Taken together, these findings identify SAA as key determinants of treatment responses in PDAC and suggest that SAA are attractive therapeutic targets in combination with PD-1 blockade + STING agonism for the treatment of PDAC.

Citation Format: Jesse Lee, Meredith L. Stone, Hana Choi, Heather Coho, Gregory L. Beatty. Serum amyloid A proteins direct therapeutic resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B029.