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

Abstract

Background 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.

Effectiveness of tislelizumab when combined with etoposide and carboplatin in patients with SMARCA4-deficient undifferentiated thoracic tumor: a case report

“…Furthermore, it can influence the outcome and effectiveness of cancer management therapies. Gantzer et al identified nine SMARCA4-UT patients and eight patients had no tertiary lymphoid structures, consistent with an immune desert TME phenotype ( 26 ). In this case, next-generation sequencing was performed and immunotherapy combined with chemotherapy was selected.…”

Thoracic SMARCA4-Deficient Undifferentiated Tumor With ALK Fusion Treated With Alectinib Achieved Remarkable Tumor Regression: Case Report

“… 3 , 9 Recent studies have found that most patients with SMARCA4-UT exhibit an immune desert tumor microenvironment, limited efficacy for immune checkpoint inhibitors, and poor prognosis. 9 , 10 Currently, most patients with SMARCA4-UT are not suitable for molecularly targeted therapies because few targetable alterations have been identified. The young woman in our case was a nonsmoker who may have a higher incidence of ALK rearrangement.…”

Clinicopathological characteristics and treatment outcomes of advanced SMARCA4‐deficient thoracic tumors

“…Renamed as “SMARCA4‐deficient undifferentiated tumor,” this tumor type distinctly differs from SMARCA4‐deficient NSCLC in phenotype 14 . Subsequent studies described SMARAC4‐UTs as highly aggressive tumors that predominantly occur in male patients with younger age and heavy smoking history 17,23,24 . Despite this, the response of SMARCA4‐UTs to PD‐1 inhibitors remains inconsistently reported and underexplored 23,24 .…”