Gaia Griguolo1,2, Anna Tosi1, Maria Vittoria Dieci1,2, Susan Fineberg3, Valentina Rossi4, Annavera Ventura1, Michele Bottosso1, Luc Bauchet5,6, Federica Miglietta1, Jack Jacob7, Valerie Rigau8, Matteo Fassan9,10, William Jacot11, PierFranco Conte1,2, Antonio Rosato1,4, Amelie Darlix12, Valentina Guarneri1,2. 1. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. 2. Division of Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy. 3. Pathology Department, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA. 4. Immunology and Molecular Oncology Diagnostics, Istituto Oncologico Veneto IRCCS, Padova, Italy. 5. Department of Neurosurgery, Gui de Chauliac Hospital - CHU, Montpellier University Medical Center, Montpellier, France. 6. Institute of Functional Genomics, Montpellier University, CNRS, INSERM, Montpellier, France. 7. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. 8. Department of Pathology, University of Montpellier, Montpellier, France. 9. Department of Medicine, Surgical Pathology Unit, University of Padova, Padova, Italy. 10. Istituto Oncologico Veneto IRCCS, Padova, Italy. 11. Medical Oncology Department, Institut du Cancer de Montpellier - University of Montpellier, Montpellier, France. 12. Medical Oncology Department, Institut du Cancer de Montpellier, Institut de Génomique Fonctionnelle, INSERM, CNRS - University of Montpellier, Montpellier, France.
Abstract
BACKGROUND: Despite potential clinical implications, the complexity of breast cancer (BC) brain metastases (BM) immune microenvironment is poorly understood. Through multiplex immunofluorescence, we here describe the main features of BCBM immune microenvironment (density and spatial distribution) and evaluate its prognostic impact. METHODS: 60 BCBM from patients undergoing neurosurgery at three institutions (2003-2018) was comprehensively assessed using two multiplex immunofluorescence panels (CD4, CD8, Granzyme B, FoxP3, CD68, pan-cytokeratin, DAPI; CD3, PD-1, PD-L1, LAG-3, TIM-3, CD163, pan-cytokeratin, DAPI). The prognostic impact of immune subpopulations and cell-to-cell spatial interactions was evaluated. RESULTS: Subtype-related differences in BCBM immune microenvironment and its prognostic impact were observed. While in HR-/HER2- BM and HER2+ BM, higher densities of intra-tumoral CD8+ lymphocytes were associated with significantly longer OS (HR 0.16 and 0.20, respectively), in HR+/HER2- BCBMs a higher CD4+FoxP3+/CD8+ cell ratio in the stroma was associated with worse OS (HR 5.4). Moreover, a higher density of intra-tumoral CD163+ M2-polarized microglia/macrophages in BCBMs was significantly associated with worse OS in HR-/HER2- and HR+/HER2- BCBMs (HR 6.56 and 4.68, respectively), but not in HER2+ BCBMs. In HER2+ BCBMs, multiplex immunofluorescence highlighted a negative prognostic role of PD-1/PD-L1 interaction: patients with a higher percentage of PD-L1+ cells spatially interacting with (within a 20 µm radius) PD-1+ cells presented a significantly worse OS (HR 4.60). CONCLUSIONS: Our results highlight subtype-related differences in BCBM immune microenvironment and identify two potential therapeutic targets, M2 microglia/macrophage polarization in HER2- and PD-1/PD-L1 interaction in HER2+ BCBMs, which warrant future exploration in clinical trials.
BACKGROUND: Despite potential clinical implications, the complexity of breast cancer (BC) brain metastases (BM) immune microenvironment is poorly understood. Through multiplex immunofluorescence, we here describe the main features of BCBM immune microenvironment (density and spatial distribution) and evaluate its prognostic impact. METHODS: 60 BCBM from patients undergoing neurosurgery at three institutions (2003-2018) was comprehensively assessed using two multiplex immunofluorescence panels (CD4, CD8, Granzyme B, FoxP3, CD68, pan-cytokeratin, DAPI; CD3, PD-1, PD-L1, LAG-3, TIM-3, CD163, pan-cytokeratin, DAPI). The prognostic impact of immune subpopulations and cell-to-cell spatial interactions was evaluated. RESULTS: Subtype-related differences in BCBM immune microenvironment and its prognostic impact were observed. While in HR-/HER2- BM and HER2+ BM, higher densities of intra-tumoral CD8+ lymphocytes were associated with significantly longer OS (HR 0.16 and 0.20, respectively), in HR+/HER2- BCBMs a higher CD4+FoxP3+/CD8+ cell ratio in the stroma was associated with worse OS (HR 5.4). Moreover, a higher density of intra-tumoral CD163+ M2-polarized microglia/macrophages in BCBMs was significantly associated with worse OS in HR-/HER2- and HR+/HER2- BCBMs (HR 6.56 and 4.68, respectively), but not in HER2+ BCBMs. In HER2+ BCBMs, multiplex immunofluorescence highlighted a negative prognostic role of PD-1/PD-L1 interaction: patients with a higher percentage of PD-L1+ cells spatially interacting with (within a 20 µm radius) PD-1+ cells presented a significantly worse OS (HR 4.60). CONCLUSIONS: Our results highlight subtype-related differences in BCBM immune microenvironment and identify two potential therapeutic targets, M2 microglia/macrophage polarization in HER2- and PD-1/PD-L1 interaction in HER2+ BCBMs, which warrant future exploration in clinical trials.
Authors: Anna Tosi; Beatrice Parisatto; Paolo Boscolo-Rizzo; Antonio Rosato; Anna Menegaldo; Giacomo Spinato; Maria Guido; Annarosa Del Mistro; Rossana Bussani; Fabrizio Zanconati; Margherita Tofanelli; Giancarlo Tirelli Journal: J Exp Clin Cancer Res Date: 2022-09-20
Authors: Davide Massa; Anna Tosi; Antonio Rosato; Valentina Guarneri; Maria Vittoria Dieci Journal: Cancers (Basel) Date: 2022-10-06 Impact factor: 6.575