Novel Molecular Determinants of Response or Resistance to Immune Checkpoint Inhibitor Therapies in Melanoma

Zhang, Wenjing; Li, Yuting; Shi, Fuyan; Lyu, Juncheng; Sheng, Chao; Wang, Shuzhen; Wang, Qinghua

doi:10.3389/fimmu.2021.798474

Cited by 10 publications

(17 citation statements)

References 57 publications

(72 reference statements)

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“…In this study, based on the integrated ICI-treated 631 melanoma and 109 NSCLC samples, we observed that HSPG2 mutations were predictive of a favorable ICI treatment outcome, which provides evidence for customizing immunotherapeutic strategies. By using the same pooled melanoma and NSCLC cohorts [ 12 , 54 , 56 ], we also discovered other mutations of the genes FAT1 , COL3A1 , NRAS , NARS2 , DCC , and PTPRT were associated with better ICI response and outcome. In addition, the ICI efficacy-related mutational signatures and molecular subtypes were also determined.…”

Section: Discussionmentioning

confidence: 94%

“…Multiple studies have revealed the potential implications of TMB for evaluating cancer immunotherapeutic efficacy [ 8 , 12 , 13 , 53 ]. However, in clinical practice, the determination of TMB needs to conduct whole-exome mutational detection [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, easier surrogates are necessary for such clinical settings. Recent research has shown that mutations in single genes, such as POLE [ 9 ], NLRP3 [ 55 ], COL3A1 [ 12 ], and PTPRT [ 54 ] could predict tumor TMB and immunotherapeutic response. In this study, HSPG2 mutations were also determined to link with an elevated mutational burden and a preferable ICI efficacy in melanoma and NSCLC, which indicates that HSPG2 mutations may be a possible indicator for TMB and cancer immune treatment response.…”

Section: Discussionmentioning

confidence: 99%

“…The above evidence demonstrated that PD-L1 expression and TMB sometimes are imperfect in predicting immunotherapeutic effects. Recently, multiple novel ICI biomarkers were reported, including gene mutations (e.g., POLE [ 9 ], JAK1/2 [ 10 ], B2M [ 10 ], and MUC16 mutations [ 11 ]), specific mutational signatures (e.g., signatures 1, 4, 7, and 11 [ 12 ]), and molecular subtypes [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer

Zhang

Lin

Shi

et al. 2022

Cancers

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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.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer

Zhang

Lin

Shi

et al. 2022

Cancers

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“…A higher TMB was demonstrated to be linked to a preferable immunotherapeutic outcome in multiple cancers [ 46 , 47 , 48 , 49 ]. However, accurate evaluation of TMB needs to perform tumor whole-exome sequencing, and cut-off values for TMB to stratify patients into high and low subgroups vary in distinct cancers [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Fatty Acid Synthase Mutations Predict Favorable Immune Checkpoint Inhibitor Outcome and Response in Melanoma and Non-Small Cell Lung Cancer Patients

Wang

Tian

Zhang

et al. 2022

Cancers

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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.

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Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma

Jackson,

Jones,

Fluke

et al. 2024

JAMA Netw Open

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ImportanceWhile smoking is associated with a decreased incidence of cutaneous melanoma, the association of smoking with melanoma progression and death is not well defined.ObjectiveTo determine the association of smoking with survival in patients with early-stage primary cutaneous melanoma.Design, Setting, and ParticipantsThis cohort study performed a post hoc analysis of data derived from the randomized, multinational first and second Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II). Participants were accrued for MSLT-I from January 20, 1994, to March 29, 2002; MSLT-II, from December 21, 2004, to March 31, 2014. Median follow-up was 110.0 (IQR, 53.4-120.0) months for MSLT-I and 67.6 (IQR, 25.8-110.2) months for MSLT-II. Patients aged 18 to 75 years with clinical stages I or II melanoma with a Breslow thickness of 1.00 mm or greater or Clark level IV to V and available standard prognostic and smoking data were included. Analyses were performed from October 4, 2022, to March 31, 2023.ExposureCurrent, former, and never smoking.Main Outcomes and MeasuresMelanoma-specific survival of patients with current, former, and never smoking status was assessed for the entire cohort and for nodal observation and among subgroups with sentinel lymph node biopsy (SLNB)–negative and SLNB-positive findings.ResultsOf 6279 included patients, 3635 (57.9%) were men, and mean (SD) age was 52.7 (13.4) years. The most common tumor location was an extremity (2743 [43.7%]), and mean (SD) Breslow thickness was 2.44 (2.06) mm. Smoking status included 1077 (17.2%) current, 1694 (27.0%) former, and 3508 (55.9%) never. Median follow-up was 78.4 (IQR, 30.5-119.6) months. Current smoking was associated with male sex, younger age, trunk site, thicker tumors, tumor ulceration, and SLNB positivity. Current smoking was associated with a greater risk of melanoma-associated death by multivariable analysis for the entire study (hazard ratio [HR], 1.48 [95% CI, 1.26-1.75]; P &lt; .001). Former smoking was not. The increased risk of melanoma-specific mortality associated with current smoking was greatest for patients with SLNB-negative melanoma (HR, 1.85 [95% CI, 1.35-2.52]; P &lt; .001), but also present for patients with SLNB-positive melanoma (HR, 1.29 [95% CI, 1.04-1.59]; P = .02) and nodal observation (HR, 1.68 [95% CI, 1.09-2.61]; P = .02). Smoking at least 20 cigarettes/d doubled the risk of death due to melanoma for patients with SLNB-negative disease (HR, 2.06 [95% CI, 1.36-3.13]; P &lt; .001).Conclusions and RelevanceThe findings of this cohort study suggest that patients with clinical stage I and II melanoma who smoked had a significantly increased risk of death due to melanoma. Smoking status should be assessed at time of melanoma diagnosis and may be considered a risk factor for disease progression.

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Novel Molecular Determinants of Response or Resistance to Immune Checkpoint Inhibitor Therapies in Melanoma

Cited by 10 publications

References 57 publications

HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer

HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer

Fatty Acid Synthase Mutations Predict Favorable Immune Checkpoint Inhibitor Outcome and Response in Melanoma and Non-Small Cell Lung Cancer Patients

Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma

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