185PD - Immunological differences between immune-rich estrogen receptor-positive and -negative breast cancers

Abstract

BackgroundA subset of estrogen receptor-positive (ER+) breast cancers have significant tumor infiltrating lymphocytes (TILs), similar to triple-negative breast cancer (TNBC). We examined differences in the immune microenvironment of immune-rich ER+ and immune-rich TNBC to find out if similar or different immunotherapy strategies are appropriate for these distinct disease types. MethodsER+/HER2-negative and TNBC cases were obtained from The Cancer Genome Atlas (TCGA) (n=818 RNA Seq) and METABRIC (n=1465 microarray). An immune gene expression score, as surrogate for TILs, was calculated for each case (Danaher et al). Signature scores were correlated with histologic TILs (R=0.44, p<0.001) for available cases. All cases in the top 25% of signature scores were considered immune-rich. We compared 22 immune cell populations between immune-rich TNBC (n=86) and ER+(n=119) using CIBERSORT (Student’s t-test, FDR adjusted). We examined differential expression of 770 immune-related genes and 137 immuno-oncology (IO) drug targets. Macrophage abundance was measured by quantitative immunofluorescence (QIF) using pan-macrophage marker CD68 in 169 TNBC and 87 ER+ FFPE tissues. ResultsIn TCGA and METABRIC, CIBERSORT showed more M0 (p=0.015, p=0.0043) and M1 macrophages (p=9.4e-08, p=6.24e-11) in immune-rich TNBC compared to ER+. Mast cells (p=0.0093, p=4.09e-15) and M2 macrophages (p=4.4e-05, p=0.053) were more abundant in immune-rich ER+. QIF confirmed higher macrophage content in TNBC (p=0.0001). In both datasets, 36 IO targets were higher expressed in TNBC and 15 in ER+ cases (Table). Notably, coordinated high expression of TGFb pathway members TGFb3, TGFb-R2, and LRRC32 was seen in ER+ cancers and correlated positively with M2 and negatively with M1 macrophage content across all cases.Table185PDTablePotential ER+ Immuno- Oncology TargetsTNBC Mean ExpressionER+ Mean ExpressionFold-Change Mean Expressionp-valueFDR-adjustedIL6ST2,71711,8154.355.13E-212.32E-19TGF-b32,0854,7452.281.32E-248.97E-23CXCR1 (IL-8 receptor A)4399882.251.04E-097.46E-09CSF3R1,0502,0251.938.46E-127.67E-11RORC1,0081,8551.843.65E-082.26E-07ADORA2A2,1633,4421.596.18E-083.65E-07LRRC32 (TGFb activator)7,54911,1521.481.09E-075.31E-07TLR38801,3001.481.65E-055.92E-05CXCL121,0551,5351.458.44E-052.53E-04CLEC14A4927051.432.68E-059.11E-05TGFb-R27,5599,8451.302.08E-045.90E-04TNFSF147998721.092.94E-036.89E-03MICA3493741.077.54E-031.51E-29NLRP33,0153,1451.043.12E-037.20E-03JAK112,68313,0581.030.0190.035 ConclusionsIO drugs targeting TGFb, M2 macrophages and mast cells are attractive therapeutic candidates in immune-rich ER+ breast cancer based on the expression characteristics of these targets. Legal entity responsible for the studyThe authors. FundingHoward Hughes Medical Institute Medical Fellows Grant. DisclosureV. Pelenkanou: Full / Part-time employment: Sanofi, US. D. Rimm: Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Agendia; Advisory / Consultancy: Biocept; Advisory / Consultancy: BMS; Advisory / Consultancy: Cell Signaling Technology; Advisory / Consultancy, Research grant / Funding (institution): Cepheid; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: GSK; Advisory / Consultancy: InVicro/Konica/Minolta; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): NanoString; Advisory / Consultancy, Research grant / Funding (institution): Perkin Elmer; Advisory / Consultancy: PAIGE.AI; Advisory / Consultancy, Research grant / Funding (institution): Ventana; Advisory / Consultancy, Research grant / Funding (institution): Ultivue; Shareholder / Stockholder / Stock options: PixelGear; Research grant / Funding (institution): Navigate/Novartis; Research grant / Funding (institution): NextCure; Research grant / Funding (institution): Lilly. L. Pusztai: Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Almac. All other authors have declared no conflicts of interest.