Qinghua Wang

SET binding protein 1 (SETBP1) plays crucial roles in various biological processes; however, its involvement in cancer immune checkpoint inhibitor (ICI) treatments has never been studied. In this study, we collected a total of 631 melanoma and 109 non-small cell lung cancer (NSCLC) samples treated with ICI agents (i.e., anti-CTLA-4, anti-PD-1/PD-L1, or combination therapy). Additionally, we obtained their corresponding somatic mutational profiles. We observed that SETBP1 mutated (SETBP1-MUT) melanoma patients exhibited significantly prolonged ICI survival outcomes compared to wild-type patients (HR: 0.56, 95% CI: 0.38-0.81, P = 0.002). Consistently, an elevated ICI response rate was also noticed in the SETBP1-MUT group (42.9% vs. 29.1%, P = 0.016). The Association of SETBP1 mutations with favorable immunotherapeutic prognosis and response was further supported by an independent NSCLC cohort (both P < 0.05). Additional immunological analyses revealed that favorable immune infiltration, tumor immunogenicity, and immune response circuits were enriched in SETBP1-MUT patients. Overall, our findings suggest that SETBP1 mutations may serve as a new biomarker for stratifying beneficiaries of ICI treatments in melanoma and NSCLC, which provides possible evidence for tailoring clinical immunotherapeutic strategies.

Remarkable clinical benefits in several advanced cancers are observed under the treatment of immune checkpoint inhibitor (ICI) agents. However, only a smaller proportion of patients respond to the treatments. Reelin (RELN) is frequently mutated in the cancer genome. In this study, the RELN mutation association with ICI treatment efficacy in melanoma and non-small cell lung cancer (NSCLC) was elucidated. Data from 631 melanoma and 109 NSCLC patients with both ICI treatment data and pre-treatment mutational profiles were collected. In addition, from the Cancer Genome Atlas (TCGA) project, we also obtained both tumors to explore the immunologic features behind RELN mutations. Melanoma patients with RELN mutations exhibited a favorable ICI survival benefit when compared with wild-type patients (HR: 0.66, 95% CI: 0.51–0.87, p = 0.003). A higher response rate was also noticed in RELN-mutated patients (38.9% vs. 28.3%, p = 0.017). The association of RELN mutations with a preferable immunotherapy outcome and response was further confirmed in NSCLC. Further exploration demonstrated that favorable immunocyte infiltration and immune response signaling pathways were found in patients with RELN mutations. In this study, RELN mutations were identified to connect with a better immune microenvironment and an improved ICI efficacy in melanoma and NSCLC, which provides a potential biomarker for immunological feature evaluation and immunotherapeutic outcome prediction at the molecular level.

Fatty acid synthase (FASN) acts as the central member in fatty acid synthesis and metabolism processes, which regulate oncogenic signals and tumor immunogenicity. To date, no studies have reported the connection of FASN mutations with ICI efficacy. In this study, from 631 melanoma and 109 NSCLC patients who received ICI treatments, we retrospectively curated multiomics profiles and ICI treatment data. We also explored the potential molecular biological mechanisms behind FASN alterations. In melanoma patients, FASN mutations were observed to associate with a preferable immunotherapeutic prognosis and response rate (both p < 0.01). These connections were further corroborated by the NSCLC patients (both p < 0.01). Further analyses showed that a favorable tumor immunogenicity and immune microenvironment were involved in FASN mutations. This work confirms the clinical immunotherapy implications of FASN mutation-mediated fatty acid metabolism and provides a possible indicator for immunotherapy prognosis prediction.

Immune checkpoint inhibitors (ICIs) markedly promote the survival outcome of advanced melanoma and non-small cell lung cancer (NSCLC). Clinically, favorable ICI treatment efficacy is noticed only in a smaller proportion of patients. Heparan sulfate proteoglycan 2 (HSPG2) frequently mutates in both tumors. Herein, we aim to investigate the immunotherapeutic and immunological roles of HSPG2 mutations in melanoma and NSCLC. A total of 631 melanoma samples and 109 NSCLC samples with both somatic mutational profiles and clinical immunotherapy data were curated. In addition, by using The Cancer Genome Atlas data, genomic and immunological traits behind HSPG2 mutations were elucidated. Melanoma patients with HSPG2 mutations had a markedly extended ICI outcome than other patients. An association between HSPG2 mutations and the improved outcome was further confirmed in NSCLC. In addition, an elevated ICI response rate was presented in HSPG2-mutated NSCLC patients (81.8% vs. 29.7%, p = 0.002). Subsequent analyses revealed that HSPG2-mutated patients had a favorable abundance of response immunocytes, an inferior abundance of suppression immunocytes, enhanced mutational burden, and interferon response-relevant signaling pathways. We uncovered that HSPG2 mutations were predictive of a better ICI response and associated with preferable immunogenicity, which may be considered as a genomic determinant to customize biotherapy strategies.

Immune checkpoint inhibitors (ICIs) are most commonly used for melanoma and non-small cell lung cancer (NSCLC) patients. FAT atypical cadherin 1 (FAT1), which frequently mutates in melanoma and NSCLC. In this study, we aim to investigate the association ofFAT1mutations with ICI response and outcome. We collected somatic mutation profiles and clinical information from ICI-treated 631 melanoma and 109 NSCLC samples, respectively. For validation, a pan-cancer cohort with 1661 patients in an immunotherapy setting was also used. Melanoma and NSCLC samples from the Cancer Genome Atlas were used to evaluate the potential immunologic mechanisms ofFAT1mutations. In melanoma, patients withFAT1mutations had a significantly improved survival outcome than those wild-type patients (HR: 0.67, 95% CI: 0.46–0.97,P = 0.033). An elevated ICI response rate also appeared inFAT1-mutated patients (43.2% vs. 29.2%,P = 0.032). Associations ofFAT1mutations with improved prognosis and ICI response were confirmed in NSCLC patients. In the pan-cancer cohort, the association betweenFAT1mutations and favorable ICI outcome was further validated (HR: 0.74, 95% CI: 0.58–0.96,P = 0.022). Genomic and immunologic analysis showed that a high mutational burden, increased infiltration of immune-response cells, decreased infiltration of immune-suppressive cells, interferon and cell cycle-related pathways were enriched in patients withFAT1mutations. Our study revealed thatFAT1mutations were associated with better immunogenicity and ICI efficacy, which may be considered as a biomarker for selecting patients to receive immunotherapy.

Background: Immune 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.Methods: We 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.Results: We 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).Conclusion: We 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.

Aging has been demonstrated to play vital roles in the prognosis and treatment efficacy of cancers, including lung adenocarcinoma (LUAD). This novel study aimed to construct an aging‐related risk signature to evaluate the prognosis and immunogenicity of LUAD. Transcriptomic profiles and clinical information were collected from a total of 2518 LUAD patients from 12 independent cohorts. The risk signature was developed by combining specific gene expression with the corresponding regression coefficients. One cohort treated with the immune checkpoint inhibitor (ICI) was also used. Subsequently, a risk signature was developed based on 21 aging‐related genes. LUAD patients with low‐risk scores exhibited improved survival outcomes in both the discovery and validation cohorts. Further immunology analysis revealed elevated lymphocyte infiltration, decreased infiltration of immune‐suppressive cells, immune response‐related pathways, and favorable ICI predictor enrichment in the low‐risk subgroup. Genomic mutation exploration indicated the enhanced mutation burden and higher mutation rates in significantly driver genes of TP53, KEAP1, SMARCA4, and RBM10 were enriched in patients with a low‐risk signature. In the immunotherapeutic cohort, it was observed that low‐risk aging scores were markedly associated with prolonged ICI prognosis. Overall, the estimated aging signature proved capable of evaluating the prognosis, tumor microenvironment, and immunogenicity, which further provided clues for tailoring prognosis prediction and immunotherapy strategies, apart from promoting individualized treatment plans for LUAD patients.

Purpose: Protein tyrosine phosphatase receptor type T (PTPRT), which is a well‐known phosphatase and mutates frequently in melanoma and non‐small cell lung cancer (NSCLC). Our research aims to elucidate its mutation association with immune checkpoint inhibitors (ICI) efficacy.Methods: We integrated whole‐exome sequencing (WES)‐based somatic mutation profiles and clinical characteristics of 631 melanoma samples received ICI agents from eight studies and 109 NSCLC samples from two studies. For validation, 321 melanoma and 350 NSCLC immunotherapy samples with targeted next‐generation sequencing (NGS) were employed. Besides, an independent NSCLC cohort contained 240 samples was also collected for further corroboration. Distinct immune infiltration was evaluated according to the PTPRT mutational status.Results: In the WES melanoma cohort, patients with PTPRT mutations harbored a significantly elevated ICI response rate (40.5% vs. 28.6%, p = 0.036) and a prolonged survival outcome (35.3 vs. 24.9 months, p = 0.006). In the WES NSCLC cohort, the favorable response and immunotherapy survival were also observed in PTPRT‐mutated patients (p = 0.036 and 0.019, respectively). For the validation cohorts, the associations of PTRPT mutations with better prognoses were identified in melanoma, NSCLC, and pan‐cancer patients with targeted‐NGS (all p < 0.05). Moreover, immunology analyses showed the higher mutation burden, increased lymphocyte infiltration, decreased‐ activated‐stroma, and immune response pathways were detected in patients with PTPRT mutations.Conclusion: Our investigation indicates that PTPRT mutations may be considered as a potential indicator for assessing ICI efficacy in melanoma and NSCLC, even across multiple cancers. Further prospective validation cohorts are warranted.

Background: Despite the acknowledged sex-related differences in immune response and immune checkpoint inhibitor (ICI) efficacy, little is known about the sex disparities in melanoma of novel genomic determinants for ICI therapies.Methods: Pretreatment genomic profiles and clinical characteristics of 631 melanoma patients treated with ICIs (i.e., inhibitors of CTLA-4, PD-1/PD-L1, or both) were comprehensively curated. Genomic factors, i.e., significantly mutated genes (SMGs), mutational signatures, and molecular subtypes were identified, and their associations with ICI treatment efficacy in male and female patients were evaluated.Results: Of the 15 SMGs identified in this study, three genes (i.e., CFH, DGKG, and PPP6C) were found to exhibit sex differences with respect to ICI efficacy. Among these, CFH mutations exhibited both response rate and survival benefits in male, but not in female patients. A total of four mutational signatures (i.e., signatures 1, 4, 7, and 11) were extracted. Male patients with signature 4 (also known as smoking-related signature) had an inferior ICI response rate and overall survival. However, this association was not significant in females. An immune subtype based on mutational activities was found to be significantly associated with poor ICI survival in female patients.Conclusion: We uncovered several sex-dependent genomic correlates of response to ICI treatment, such as male-biased CFH mutations and signature 4 and the female-biased immune resistance subtype. The findings derived from this research provide clues for exploring different immunotherapeutic approaches in male and female patients with melanoma.