Immune-Desert Tumor Microenvironment in Thoracic SMARCA4-Deficient Undifferentiated Tumors with Limited Efficacy of Immune Checkpoint Inhibitors

Justine Gantzer (1) , Guillaume Davidson (2) , Bujamin Vokshi , Noëlle Weingertner (3) , Antoine Bougoüin (4) , Marco Moreira (4) , Véronique Lindner , Guillaume Lacroix (4) , Céline Mascaux (5) , Marie-Pierre Chenard (6) , F. Bertucci (7) , Irwin Davidson (2) , Jean-Emmanuel Kurtz (8) , Catherine Sautès-Fridman (4) , Wolf Fridman (4) , Gabriel Malouf (2)

1 ICANS - Institut de Cancérologie de Strasbourg Europe
2 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
3 Département de pathologie
4 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
5 IRFAC - Inserm U1113 - Interface de Recherche Fondamentale et Appliquée en Cancérologie
6 Service de pathologie [CHU Strasbourg]
7 CRCM - Centre de Recherche en Cancérologie de Marseille
8 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]

Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive neoplasms. Data linking BAF alterations with tumor microenvironment (TME) and efficacy of immune checkpoint inhibitors (ICI) are contradictory. The TME of SMARCA4-UT and their response to ICI are unknown. Materials and Methods Patients diagnosed with SMARCA4-UT in our institution were included. Immunostainings for tertiary lymphoid structures (TLS), immune cell markers, and checkpoints were assessed. Validation was performed using an independent transcriptome dataset including SMARCA4-UT, non–small cell lung cancers (NSCLC) with/without SMARCA4 mutations, and unclassified thoracic sarcomas (UTS). CXCL9 and PD-L1 expressions were assessed in NSCLC and thoracic fibroblast cell lines, with/without SMARCA4 knockdown, treated with/without interferon gamma. Results Nine patients were identified. All samples but one showed no TLS, consistent with an immune desert TME phenotype. Four patients received ICI as part of their treatment, but the only one who responded, had a tumor with a TLS and immune-rich TME. Unsupervised clustering of the validation cohort using immune cell scores identified 2 clusters associated with cell ontogeny and immunity (cluster 1 enriched for NSCLC independently of SMARCA4 status (n = 9/10; P = .001); cluster 2 enriched for SMARCA4-UT (n = 11/12; P = .005) and UTS (n = 5/5; P = .0005). SMARCA4 loss-of-function experiments revealed interferon-induced upregulation of CXCL9 and PD-L1 expression in the NSCLC cell line with no effect on the thoracic fibroblast cell line. Conclusion SMARCA4-UT mainly have an immune desert TME with limited efficacy to ICI. TME of SMARCA4-driven tumors varies according to the cell of origin questioning the interplay between BAF alterations, cell ontogeny and immunity.

Domaines: Cancer

Justine Gantzer, Guillaume Davidson, Bujamin Vokshi, Noëlle Weingertner, Antoine Bougoüin, et al.. Immune-Desert Tumor Microenvironment in Thoracic SMARCA4-Deficient Undifferentiated Tumors with Limited Efficacy of Immune Checkpoint Inhibitors. Oncologist, 2022, ⟨10.1093/oncolo/oyac040⟩. ⟨hal-03623495⟩