864 Exploration of the circulating immune microenvironment stratified by breast cancer subtype

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Background Hormone receptor-positive (HR+) HER2-, HER2 enriched (HER2+), and triple negative breast carcinoma (TNBC) are different molecular intrinsic subtypes of breast cancer (BC). While each subtype has distinct tumor immunogenicity features, how this translates into the circulating immune composition is unknown. This study explored potential differences in the circulating immune system between metastatic HR+HER2-, HER2+ and metastatic TNBC patients. Methods PBMCs were subjected to immune profiling using flow cytometry. Normal donor (ND) PBMC (n=4) serve as controls for HR+HER2- BC (n=18), HER2+ BC (n=19) and TNBC (n=17) patient samples. TGFb isoforms were assessed in plasma from HR+HER2- BC (n=6), HER2+ BC (n=7) and TNBC (n=6) patients. Statistical tests performed are Kruskal-Wallis test for flow cytometry data and ordinary one-way ANOVA, multiple comparison for TGFβ assessment. Histologic grading was performed by a pathologist for all cases. Results Compared to ND control, HR+HER2- BC have decreased CD4+ T cells and CD8+ T cells (p<0.05), increased Treg cells (p<0.05), increased CTLA4, ICOS expressions on CD4+ T cells, CD8+ T cells and NK cells (p<0.05), decreased HLA-DR expressions on DCs and monocytes (p<0.05), and decreased CD86 expression on DCs (p<0.05);TNBC have decreased HLA-DR expression on DCs and monocytes (p<0.05); HER2+BC have decreased CD86 expression on DCs (p<0.05). Pairwise comparison revealed that HR+HER2- BC have decreased CD3+ T cells and CD4+ T cells (p<0.01), increased CTLA4, ICOS and Ki67 expressions in CD4+ T cells, CD8+ T cells and NK cells (p<0.05), increased Treg frequencies (p<0.05), increased Tim3 expression on NK cells (p<0.05), and increased myeloid frequencies (p<0.05), as compared to HER2+ BC; TNBC displayed increased Treg frequencies (p<0.05), increased Ki67 expression in CD4+ T cells, CD8+ T cells and NK cells (p<0.05) compared to HER2+ BC; however, TNBC have decreased CTLA4 expression on CD4+ T cells and CD8+ T cells (p<0.01), and decreased Tim3 expression on NK cells (p<0.001) compared to HR+HER2- BC. While no statistical associations were found based upon pathologic tumor grading, ICOS expression was only detected on NK cells and CD4+ T cells from poorly differentiated HER2+ BC. TGFb3 concentration, but not TGFb1 and TGFb2 concentrations, is significantly higher in HR+HER2- BC than in HER2+ BC (p<0.05) and positively correlates with Treg frequencies in HR+HER2- BC. Conclusions Metastatic HR+HER2- BC has the most suppressive circulating immune-microenvironment followed by metastatic TNBC with non-metastatic HER2+ BC having the least suppressive circulating immune-microenvironment. Ongoing efforts include expanding this study to include metastatic HER2+ BC cases. Acknowledgements This study was supported by the MDA – Merck KGaA Strategic Alliance, the NIH CCSG Award (CA016672 (Institutional Tissue Bank (ITB), Research Histology Core Laboratory (RHCL) and ORION core), Adaptive Patient-Oriented Longitudinal Learning and Optimization (APOLLO) Moonshot Program, Strategic Alliances and the Translational Molecular Pathology-Immunoprofiling (TMP-IL) Moon Shots Platform at the Department Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center. We would like to thank the patients who consented to be included in the study. Ethics Approval Patients consented to MD Anderson Cancer Center IRB approved protocols: 2017-0499, 2017-0500, and 2017-0502.

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