Abstract 979: Programmed death-ligand 1 expression and tumor-infiltrating immune cells in cancers associated with Li-Fraumeni syndrome

Abstract

Abstract Purpose: Li-Fraumeni syndrome (LFS), due to TP53 germline mutations, is characterized by high incidence of multiple cancers. Dysregulation of the TP53 pathway is associated with changes in chemokine production and reduced tumor immune infiltration in some cancer types. Recent works also suggested that TP53 negatively regulates PDL1 expression through the non-coding RNA miR-34. To better understand immune evasion of LFS spectrum cancers and to explore the feasibility of PD1/PDL1 targeted therapies as an alternative to genotoxic treatments in LFS patients, we investigated a range of LFS-related tumor types for PDL1 expression and tumor-infiltrating immune cells. Methods: We retrospectively collected a total of 72 tumor samples (osteosarcoma=32, rhabdomyosarcoma=11, adrenocortical carcinoma=11 and breast carcinoma=18) from 60 pediatric and adult patients identified through the LFS French database and direct contact with oncologic centers. Immunochemistry analyses were performed on whole slide sections. PDL1 staining was performed using the clone E1L3N (Cell Signaling Technology) according to the standard automated protocols. Immune infiltrate was characterized by the following antibody panel: CD8, FOXP3 and CD68. For CD8+ and FoxP3+ T cells, cell density per surface unit was determined by cell counting; for CD68+ macrophages, a semi-quantitative scoring (from 0 to 4) was performed. Results: Median age of patients was 13 years (range: 6-23) for osteosarcoma, 1.7 years (range: 0.8-5) for rhabdomyosarcoma, 2.3 years (range: 0.4-6) for adrenocortical carcinoma and 27.5 years (range: 22-54) for breast carcinoma. Seven patients presented ≥2 metachronous tumors. Biopsy was performed at diagnosis for 68 patients, at relapse for 3 patients and at early progression for one patient. None of the samples presented any detectable PDL1 expression neither on tumor cells nor on tumor microenvironment. Low/very low amount of CD8+ cytotoxic T-cells was displayed, regardless of the histology. FoxP3+ regulatory T-cell infiltration varied among tumor types. Thirty-five/72 tumors (49%) did not contain regulatory T cells. Breast carcinomas presented significant amounts of regulatory T cells (16/18, 89%), but at low density for 10 out of 16 samples (62%). Sixty-two/72 tumors (86%) presented CD68+ macrophage infiltrates, with high density in 37/62 (60%) of them (score ≥ 2+). Conclusion: The absence of PDL1 expression on tumor cells and microenvironment as well as the low amount of regulatory T cells do not support the hypothesis of PDL1 induction through p53 inactivation in LFS. The role of innate immunity needs to be explored to identify alternative immunological targets. Citation Format: Emilie Saucier, Claudia Pasqualini, Louise Galmiche, Frédérique Larousserie, Marie Karanian, Véronique Minard-Colin, Birgit Geoerger, Dominique Valteau-Couanet, Laurence Brugières, Jean-Yves Scoazec. Programmed death-ligand 1 expression and tumor-infiltrating immune cells in cancers associated with Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 979.