Impact Of Arid1a Mutation On The Tumor Microenvironment Of Advanced Clear Cell Ovarian Cancer.

Abstract Treatment of advanced Clear Cell Ovarian Cancer (CCOC) with immune checkpoint inhibition (ICI) is currently undergoing evaluation in a Phase II clinical trial. ARID1A mutations, which occur in up to 57% of CCOC, influence immune cell infiltration in pre-clinical models, but more information is needed on how it alters the tumor microenvironment (TME) of human CCOC. Methods: FFPE samples from 36 cases of FIGO III-IV CCOC were analyzed. Of the 36 cases; 21 were ARID1A wildtype (ARID1Awt), 14 ARID1A mutant (ARID1Amut) and 1 mixed. Immunohistochemistry was performed for immune markers (CD3, CD8, CD4, CD45RO, FOXP3, CD20, CD68, CD1a, Mast Cell Tryptase, Eosinophil Derived Neurotoxin, alpha-SMA) alongside PD1, PDL1, PDL2 and quantified using QuPath. The malignant cell area (MCA), leading edge (LE) and stroma were measured separately to provide information on immune marker location within the TME. Collagen was identified by Masson's Trichrome with structural analysis using the FIJI plugin TWOMBLI. Statistical analysis was performed on PRISM. Results: In this study we found significant differences between the TME of ARID1Awt and ARID1Amut tumors in terms of both immune infiltrate, collagen density and structure. ARID1Awt tumors had more collagen, with longer fibers and more branchpoints across the MCA, LE and Stroma (<0.05). Within the LE and Stroma of ARID1Awt tumors, collagen fibers formed a more diffuse isotropic matrix (<0.05). There were significant differences at the 0.05 level for all immune markers between ARID1Awt and ARID1Amut tumors apart from CD68. The LE of ARID1Amut was the most immune rich region, with the largest populations of CD3 and CD45RO T-cells, CD20 B-cells and Mast Cells. The LE of ARID1Awt tumors had the largest populations of CD4 and FOXP3 T-Cells. There were significantly more CD8 T-cells within the MCA of ARID1Amut tumors and significantly more at the LE and within the stroma of ARID1Awt (p=<0.001). Across the MCA, LE and stroma of both groups, there was significantly more PDL2 than either PD1 or PDL1 (p=<0.0001). In ARID1Amut tumors there was significantly more PDL1 expression within the MCA compared to ARID1Awt tumors, which had more PD-1 at the LE and significantly more PDL2 within both the MCA and LE (p=<0.05). Conclusion: There are significant differences in the collagen matrix, immune cell populations and the PD1-PDL1-PDL2 axis between ARID1Awt and ARID1Amut advanced CCOC tumors. This may influence response to ICI and other therapies. Citation Format: Michael-John Devlin, Rebecca S. Kristeleit, Jacqueline McDermott, Eleni Maniati, Florian Laforêts, Panoraia Kotantaki, Rowan Miller, Frances Balkwill. Impact of ARID1A mutation on the tumor microenvironment of advanced clear cell ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2748.