Immune microenvironment characterisation and dynamics during anti-HER2-based neoadjuvant treatment in HER2-positive breast cancer

Taca de plasma sec; Hepatitis C; Targeta de separació de plasma Mancha de plasma seco; Hepatitis C; Tarjeta de separación de plasma Dried plasma spot; Hepatitis C; Plasma separation card Despite their recognised role in HER2-positive (HER2+) breast cancer (BC), the composition, localisation and functional orientation of immune cells within tumour microenvironment, as well as its dynamics during anti-HER2 treatment, is largely unknown. We here investigate changes in tumour-immune contexture, as assessed by stromal tumour-infiltrating lymphocytes (sTILs) and by multiplexed spatial cellular phenotyping, during treatment with lapatinib-trastuzumab in HER2+ BC patients (PAMELA trial). Moreover, we evaluate the relationship of tumour-immune contexture with hormone receptor status, intrinsic subtype and immune-related gene expression. sTIL levels increase after 2 weeks of HER2 blockade in HR-negative disease and HER2-enriched subtype. This is linked to a concomitant increase in cell density of all four immune subpopulations (CD3+, CD4+, CD8+, Foxp3+). Moreover, immune contexture analysis showed that immune cells spatially interacting with tumour cells have the strongest association with response to anti-HER2 treatment. Subsequently, sTILs consistently decrease at the surgery in patients achieving pathologic complete response, whereas most residual tumours at surgery remain inflamed, possibly reflecting a progressive loss of function of T cells. Understanding the features of the resulting tumour immunosuppressive microenvironment has crucial implications for the design of new strategies to de-escalate or escalate systemic therapy in early-stage HER2+ BC. We thank all the patients and family members for participating in the PAMELA study. This study was supported, in part, by Instituto de Salud Carlos III—PI16/00904, The Breast Cancer Research Foundation and Fundación Científica Asociación Española Contra el Cáncer (Ayuda Postdoctoral AECC 2017), Fundación Merck—Immunología and Comprehensive Programme of Cancer Immunotherapy & Immunology (CAIMI) BBVA Foundation (grant number 89/2017). Acknowledgements to the Cellex Foundation for providing research facilities and equipment. G.G. acknowledges funding from a 2019 Conquer Cancer Foundation YIA in Breast Cancer. This work has been realised in the Surgery and Morphological Sciences Doctorate framework of Univ Autonoma de Barcelona.