Antibodies as biomarker candidates for response and survival to checkpoint inhibitors in melanoma patients

Fässler, Mirjam; Diem, Stefan; Mangana, Joanna; Ali, Omar Hasan; Berner, Fiamma; Bomze, David; Ring, Sandra S.; Niederer, Rebekka; Gil‐Cruz, Cristina; Shibayama, Christian Ivan Pérez; Królik, Michał; Siano, Marco; Joerger, Markus; Recher, Mike; Risch, Lorenz; Güsewell, Sabine; Risch, Martin; Speiser, Daniel E.; Ludewig, Burkhard; Levesque, Mitchell P.; Dummer, Reinhard; Flatz, Lukas

doi:10.1186/s40425-019-0523-2

Cited by 53 publications

(52 citation statements)

References 55 publications

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“…MART-1, which is encoded by MLANA, contains a peptide that is presented by MHC-I and efficiently recognized by T cells [38]. In addition, other pigmentation markers including TYR and DCT serve as melanoma antigens [39]. Accordingly, when melanomas are driven into dedifferentiation, they can more easily escape T cell control [11].…”

Section: Discussionmentioning

confidence: 99%

The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

et al. 2020

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The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.

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Section: Discussionmentioning

confidence: 99%

The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

et al. 2020

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“…Evidence of B cell mediated cytotoxicity via granzyme B and TRAIL has been shown in hepatocellular carcinoma ( 83 ). IgG class antibodies have been found to be tumor-specific, and this has been reported in melanoma ( 75 ) and other cancer types and has been correlated with a favorable prognosis ( 84 – 87 ).…”

Section: Antibody Responses In Melanomamentioning

confidence: 88%

B Cells in Patients With Melanoma: Implications for Treatment With Checkpoint Inhibitor Antibodies

et al. 2021

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The contributions of the humoral immune response to melanoma are now widely recognized, with reports of positive prognostic value ascribed to tumor-infiltrating B cells (TIL-B) and increasing evidence of B cells as key predictors of patient response to treatment. There are disparate views as to the pro- and anti-tumor roles of B cells. B cells appear to play an integral role in forming tumor-associated tertiary lymphoid structures (TLSs) which can further modulate T cell activation. Expressed antibodies may distinctly influence tumor regulation in the tumor microenvironment, with some isotypes associated with strong anti-tumor immune response and others with progressive disease. Recently, B cells have been evaluated in the context of cancer immunotherapy. Checkpoint inhibitors (CPIs), targeting T cell effector functions, have revolutionized the management of melanoma for many patients; however, there remains a need to accurately predict treatment responders. Increasing evidence suggests that B cells may not be simple bystanders to CPI immunotherapy. Mature and differentiated B cell phenotypes are key positive correlates of CPI response. Recent evidence also points to an enrichment in activatory B cell phenotypes, and the contribution of B cells to TLS formation may facilitate induction of T cell phenotypes required for response to CPI. Contrastingly, specific B cell subsets often correlate with immune-related adverse events (irAEs) in CPI. With increased appreciation of the multifaceted role of B cell immunity, novel therapeutic strategies and biomarkers can be explored and translated into the clinic to optimize CPI immunotherapy in melanoma.

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“…One study showed that patients with GC had a worse prognosis if they were positive for more than 2 antibodies in the panel of TP53, heat shock protein 70, p90, HCC-22-5, KM-HN-1, and peroxiredoxin VI ( 38 ). Another study showed that high levels of antibodies against TRP1/TYRP1, TRP2/TYRP2, gp100, and Melan/MART1 may be useful metastatic biomarkers for melanoma ( 41 ). Therefore, the serial serum samples from 23 patients with GAC were detected to investigate the temporal changes of these autoantibodies in this study.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Validation of Serum Autoantibodies Against Tumor-Associated Antigens as Biomarkers in Gastric Adenocarcinoma Based on the Focused Protein Arrays

Yang

Qin

Sun

et al. 2020

Clin Transl Gastroenterol

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INTRODUCTION: Previous studies have demonstrated that autoantibodies against tumor-associated antigens (TAAs) in patients with cancer can be used as sensitive immunodiagnostic biomarkers for the detection of cancer. Most of these TAAs are involved in the tumorigenesis pathway. Cancer driver genes with intragenic mutations can promote tumorigenesis. This study aims to identify autoantibodies against TAAs encoded by cancer driver genes in sera as potential immunodiagnostic biomarkers for gastric adenocarcinoma (GAC). METHODS: Protein arrays based on cancer driver genes were customized for screening candidate TAAs in 100 GAC sera and 50 normal control (NC) sera. Autoantibodies against candidate TAAs were assessed by enzyme-linked immunosorbent assay in both training group (205 GAC sera and 205 NC sera) and independent validation group (126 GAC sera and 126 NC sera). Moreover, the immunodiagnostic models were respectively established and validated in the training group and validation group. RESULTS: A panel with 5 autoantibodies including anti-TP53, anti-COPB1, anti-GNAS, anti–serine/arginine-rich splicing factor 2, and anti-SMARCB1 was selected by the Fisher linear discriminant analysis model with an areas under receiver operating characteristic curve (AUC) of 0.928 (95% confidence interval [CI]: 0.888–0.967) in the training cohort and an AUC of 0.885 (95% CI: 0.852–0.918) in the validation cohort. Besides, the panel with 5 autoantibodies including anti-TP53, anti-COPB1, anti-GNAS, anti-PBRM1, and anti-ACVR1B which were selected by the binary logistic regression model showed an AUC of 0.885 (95% CI: 0.852–0.919) in the training cohort and 0.884 (95% CI: 0.842–0.925) in the validation cohort. DISCUSSION: Two panels which were selected in this study could boost the detection of anti-TAA autoantibodies in sera as biomarkers for the detection of GAC.

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Antibodies as biomarker candidates for response and survival to checkpoint inhibitors in melanoma patients

Cited by 53 publications

References 55 publications

The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

B Cells in Patients With Melanoma: Implications for Treatment With Checkpoint Inhibitor Antibodies

Discovery and Validation of Serum Autoantibodies Against Tumor-Associated Antigens as Biomarkers in Gastric Adenocarcinoma Based on the Focused Protein Arrays

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