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Xevinapant plus chemoradiotherapy negatively sculpts the tumour immune microenvironment in head and neck cancer

ABSTRACT: Xevinapant is an orally bioavailable antagonist of select members of the inhibitor of apoptosis protein (IAP) family. Despite promising initial data, combining xevinapant with chemoradiation (CRT) failed to improve outcomes in the TrilynX phase III trial for locally-advanced head and neck squamous cell cancer (SCCHN). We investigated the addition of xevinapant to CRT in immunocompetent mouse models of SCCHN and found maintained or improved locoregional control in vivo in a CD8+ T-cell-independent manner. In mEER, numbers of tumour-infiltrating cytotoxic CD8+ T-cells and NK cells were reduced, with remaining CD8+ T-cells characterised by PD-1hi CD38hi expression and Nr4a3 dynamics consistent with non-responsiveness to antigenic re-stimulation. Furthermore, xevinapant plus CRT significantly downregulated gene expression associated with immune-related pathways, increased levels of immunodysregulatory acute phase proteins and decreased levels of necroptosis mediator RIPK3. Overall, xevinapant plus CRT has an immunosuppressive effect on the tumour-immune microenvironment which may explain its lack of clinical benefit.

ORGANISM(S): Mus musculus

PROVIDER: GSE297026 | GEO | 2025/10/16

REPOSITORIES: GEO

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Project description:Importance: Neoadjuvant chemoradiotherapy (CRT) is the standard of care for advanced rectal cancer. Yet, predicting response to CRT remains an unmet clinical challenge. Objective: To investigate the transcriptomic determinants to predict response to neoadjuvant CRT and survival in patients with advanced rectal cancer. Design: A single-center, retrospective, cohort study. Setting: A comprehensive cancer center. Participants: Pre-treatment biopsies from 298 patients with rectal cancer, who were later treated with neoadjuvant CRT between 2004 and 2020, were analyzed by RNA sequencing. Main measures and outcomes: Transcriptional subtyping was performed by consensus molecular subtype (CMS) classification. Immune cell infiltration was assessed using MCP-counter scores and single-sample gene set enrichment analysis (ssGSEA). Patients with surgical specimens of tumor regression grade (TRG) 3-4 or who were managed by the watch-and-wait approach for more than 3 years were defined as good responders. Results: Patients classified as CMS1 (6.4%) had a significantly higher rate of good responders; albeit survival was comparable among the four subtypes. Good responders exhibited an enrichment in various immune-related pathways (IFNg and a responses, allograft rejection, IL6 STAT3 signaling during acute phase response, and inflammation), as determined by ssGSEA. MCP-counter scores for cytotoxic lymphocytes were significantly higher for good responders than non-responders (p = 0.0003), and significantly higher for responders than non-responders in GSE109057 (p = 0.0137), GSE87211 (p = 0.0092), and GSE45404 (p = 0.0327) datasets. Cytotoxic lymphocyte MCP-counter score was thus considered an independent predictor of response to CRT, as determined in the multivariable Cox analysis (OR 3.810 [95% CI 1.820-7.970]; p = 0.0004). Multivariable Cox analysis, including post-operative pathological factors, revealed cytotoxic lymphocyte MCP-counter score to be independently associated with recurrence-free survival (HR 0.382 [95% CI 0.158-0.923]; p = 0.0325) and overall survival (HR 0.157 [95% CI 0.030-0.827]; p = 0.0290). ssGSEA showed significantly higher levels of four subpopulations of cytotoxic cells (effector memory CD8 T, natural killer T, natural killer, and activated CD8 T cells) among good responders than non-responders. Conclusions and Relevance: Cytotoxic lymphocyte score, as computed by RNA sequencing, could be a useful marker for predicting response to CRT and survival among patients with rectal cancer.

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Xevinapant plus chemoradiotherapy negatively sculpts the tumour immune microenvironment in head and neck cancer

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