Abstract
BackgroundImmune checkpoint inhibitor (ICI) therapy dramatically prolongs melanoma survival. Currently, the identified ICI markers are sometimes ineffective. The objective of this study was to identify novel determinants of ICI efficacy.MethodsWe comprehensively curated pretreatment somatic mutational profiles and clinical information from 631 melanoma patients who received blockade therapy of immune checkpoints (i.e., CTLA-4, PD-1/PD-L1, or a combination). Significantly mutated genes (SMGs), mutational signatures, and potential molecular subtypes were determined. Their association with ICI responses was assessed simultaneously.ResultsWe identified 27 SMGs, including four novel SMGs (COL3A1, NRAS, NARS2, and DCC) that are associated with ICI efficacy and well-known driver genes. COL3A1 mutations were associated with improved ICI overall survival (hazard ratio (HR): 0.64, 95% CI: 0.45–0.91, p = 0.012), whereas immune resistance was observed in patients with NRAS mutations (HR: 1.42, 95% CI: 1.10–1.82, p = 0.006). The presence of the tobacco smoking-related signature was significantly correlated with inferior prognoses (HR: 1.42, 95% CI: 1.11–1.82, p = 0.005). In addition, the signature resembling that of alkylating agents and a newly discovered signature both exhibited extended prognoses (both HR < 1, p < 0.05). Based on the activities of the extracted 6 mutational signatures, we identified one immune subtype that was significantly associated with better ICI outcomes (HR: 0.44, 95% CI: 0.23–0.87, p = 0.017).ConclusionWe uncovered several novel SMGs and re-annotated mutational signatures that are linked to immunotherapy response or resistance. In addition, an immune subtype was found to exhibit favorable prognoses. Further studies are required to validate these findings.
Highlights
The blockade of cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death-1 (PD-1), or its ligand PD-L1 with monoclonal antibodies considerably prolongs the survival of patients with advanced or metastatic melanoma [1]
By integrating mutational profiles and clinicopathologic characteristics across 631 samples, we aimed to identify novel significantly mutated genes (SMGs) and potential immune subtypes that are associated with response or resistance to immune checkpoint inhibitors (ICIs) treatment and to re-annotate the mutational signatures in the setting of immunotherapy
The results demonstrated that elevated Tumor mutational burden (TMB) was significantly correlated with improved ICI overall survival (OS) and progression-free survival (PFS) in multivariate Cox regression models (p < 0.001 and p = 0.065, respectively; Figures S3A, B)
Summary
The blockade of cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death-1 (PD-1), or its ligand PD-L1 with monoclonal antibodies (e.g., ipilimumab, pembrolizumab, or nivolumab) considerably prolongs the survival of patients with advanced or metastatic melanoma [1]. Despite impressive durable clinical benefits, immune checkpoint inhibitors (ICIs) offer a long-term response only to a subset of patients with melanoma [3]. Initial clinical trials of anti-PD-1 showed that tumors expressing high PD-L1 levels were associated with benefits to treatment [4,5,6]. Tumor mutational burden (TMB) is consistently correlated with elevated benefits to ICI agents, initially in trials of melanoma and non-small cell lung cancer (NSCLC) [10,11,12]. The association of high TMB with improved ICI response has been observed in several other cancers [13,14,15]. Immune checkpoint inhibitor (ICI) therapy dramatically prolongs melanoma survival. The objective of this study was to identify novel determinants of ICI efficacy
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
