General Surgery Resident University of Rochester Medical Center Rochester, New York, United States
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Participants should be aware of the following financial/non-financial relationships:
Paul R. Burchard, MD: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Introduction: Prognosis remains poor for cholangiocarcinoma (CCA) due to a highly immunosuppressive fibro-inflammatory stroma. Lysyl oxidases (LOX) consist of 5 secreted enzymes that increase tumor stroma density and impair anti-tumor immunity. Here, we present our findings of pan-LOX inhibition with a novel agent in a murine model of CCA.
Methods: Immunohistochemistry (IHC) analysis was performed on human and spontaneous murine CCA. Spontaneous murine CCA was screened for disease onset with ultrasonography and mice were enrolled into treatment groups of 5-FU + Oxaliplatin (FOX) with or without PXS-5505. A syngeneic CCA cell line derived from spontaneous murine CCA was surgically implanted into livers of C57BL/6 mice followed by enrollment into treatment groups of FOX and FOX + PXS-5505. Flow cytometry analysis of myeloid and T-cell populations was performed with single-cell tumor suspensions.
Results: IHC analysis of spontaneous and orthotopic murine CCA tumors revealed elevated collagen deposition, fibroblast activation, and inflammatory leukocyte infiltrate, similar to human CCA. Spontaneous murine CCA exhibited delayed tumor growth (p < 0.0001) and onset of ascites (p=0.005) with improved survival (median 76 vs. 59 days, p=0.006) after treatment with FOX + PXS-5505 compared to FOX alone. Flow cytometry analysis orthotopic tumors treated with FOX + PXS-5505 revealed decreased levels of CD11b+ myeloid cells (p=0.008), monocytic and granulocytic myeloid-derived suppressor cells (p=0.002 and p=0.01, respectively), and tumor associated macrophages (TAMs; p=0.02) compared to FOX alone (Figure 1A). Arg1+ and PD-L1+ TAMs were also decreased after treatment with FOX + PXS-5505 (p=0.02 and p=0.03) (Figure 1B) while CD3+ (p=0.006) and CD4+ (p=0.01) T-cells were increased. FOX + PXS-5505 treated tumors contained fewer FoxP3+CD4 (Treg) cells (p=0.0002) and increased CD8:Treg cells (p=0.0006).
Conclusions: Combination therapy of PXS-5505 with FOX decreased CCA progression and improved survival in spontaneous murine CCA. Improved tumor control was associated with reduced myeloid suppression. Combination therapy with PXS-5505 represents an innovative therapeutic strategy for clinical translation.
Learning Objectives:
Upon completion, participant will be able to discuss mechanisms of immunosuppression in cholangiocarcinoma.
Upon completion, participant will be able to describe the histologic features of cholangiocarcinoma.
Upon completion, participant will be able to describe PXS-5505 and its novel mechanism of action.
