Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions

Sucker, Antje; Zhao, Fang; Pieper, Natalia; Heeke, Christina; Maltaner, Raffaela; Stadtler, Nadine; Real, Birgit; Bielefeld, Nicola; Howe, Sebastian; Weide, Benjamin; Gutzmer, Ralf; Utikal, Jochen; Loquai, Carmen; Gogas, Helen; Klein-Hitpaß, Ludger; Zeschnigk, Michael; Westendorf, Astrid M.; Trilling, Mirko; Horn, Susanne; Schilling, Bastian; Schadendorf, Dirk; Griewank, Klaus G.; Paschen, Annette

doi:10.1038/ncomms15440

Cited by 210 publications

(186 citation statements)

References 63 publications

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“…These tumour cells express low levels of HLA class I molecules that cannot be up‐regulated. Another example of this irreversible molecular mechanism was recently reported in melanoma . Soft lesions include the down‐regulation of HLA class I antigens by defects in the gene regulation of HLA class I heavy chain genes, β 2 ‐microgobulin gene and components of the antigen‐processing machinery.…”

Section: Cancer Immunotherapy: Impact Of ‘Soft’ and ‘Hard’ Hla Classmentioning

confidence: 92%

“…In Caki‐2 renal cell carcinoma cells, resistance to IFNs resulted from the absence of DNA binding activity for IFN regulatory factor‐1 and for STAT‐1 . Dr Annette Paschen and co‐workers at the University of Essen recently reported genetic defects in the IFN signalling pathway in a large number of melanoma cell lines derived from metastatic lesions and showed that HLA class I expression was impaired by these alterations …”

Section: Mhc/hla Class I Expression During the Natural History Of Tummentioning

confidence: 99%

“…54 Dr Annette Paschen and coworkers at the University of Essen recently reported genetic defects in the IFN signalling pathway in a large number of melanoma cell lines derived from metastatic lesions and showed that HLA class I expression was impaired by these alterations. 55…”

Section: Metastases Resistant To Hla Up-regulation Because Of Mutatiomentioning

confidence: 99%

“…Another example of this irreversible molecular mechanism was recently reported in melanoma. 55 Soft lesions include the down-regulation of HLA class I antigens by defects in the gene regulation of HLA class I heavy chain genes, b 2 -microgobulin gene and components of the antigen-processing machinery. These abnormal HLA class I phenotypes have low mRNA levels of these genes, which appear to be co-ordinately downregulated and can be corrected in vitro and in vivo by treatment with T helper type 1 cytokines.…”

Section: Cancer Immunotherapy: Impact Of 'Soft' and 'Hard' Hla Classmentioning

confidence: 99%

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Cancer immune escape: MHC expression in primary tumours versus metastases

2019

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Summary Tumours can escape T‐cell responses by losing major histocompatibility complex (MHC)/ human leucocyte antigen (HLA) class I molecules. In the early stages of cancer development, primary tumours are composed of homogeneous HLA class I‐positive cancer cells. Subsequently, infiltration of the tumour by T cells generates a vast diversity of tumour clones with different MHC class I expressions. A Darwinian type of T‐cell‐mediated immune selection results in a tumour composed solely of MHC class I‐negative cells. Metastatic colonization is a highly complex phenomenon in which T lymphocytes and natural killer cells play a major role. We have obtained evidence that the MHC class I phenotype of metastatic colonies can be highly diverse and is not necessarily the same as that of the primary tumour. The molecular mechanisms responsible for MHC/HLA class I alterations are an important determinant of the clinical response to cancer immunotherapy. Hence, immunotherapy can successfully up‐regulate MHC/HLA class I expression if the alteration is reversible (‘soft’), leading to T‐cell‐mediated tumour regression. In contrast, it cannot recover this expression if the alteration is irreversible (‘hard’), when tumour cells escape T‐cell‐mediated destruction with subsequent cancer progression. This review summarizes clinical and experimental data on the complexity of immune escape mechanisms used by tumour cells to avoid T and natural killer cell responses. We also provide in‐depth analysis of the nature of MHC/HLA class I changes during metastatic colonization and contribute evidence of the enormous diversity of MHC/HLA class I phenotypes that can be produced by tumour cells during this process.

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Section: Cancer Immunotherapy: Impact Of ‘Soft’ and ‘Hard’ Hla Classmentioning

confidence: 92%

Section: Mhc/hla Class I Expression During the Natural History Of Tummentioning

confidence: 99%

Section: Metastases Resistant To Hla Up-regulation Because Of Mutatiomentioning

confidence: 99%

Section: Cancer Immunotherapy: Impact Of 'Soft' and 'Hard' Hla Classmentioning

confidence: 99%

See 2 more Smart Citations

Cancer immune escape: MHC expression in primary tumours versus metastases

2019

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“…Here, we used experimental and mathematical models of ACT in order to compare the evolution of gene edited Pmel antigen loss variants (Pmel knockout; Pmel KO ) with adaptive dedifferentiation, because genetically hardwired loss of target antigen expression or presentation is another key mechanism of resistance to immunotherapy (Restifo et al, 1996;Sucker et al, 2017;Zaretsky et al, 2016). ACT strongly selected for Pmel KO melanoma cells, but unexpectedly they exhibited a growth defect in the absence of therapy imposed by the bulk wild-type (WT) melanoma cell population.…”

Section: Introductionmentioning

confidence: 99%

Experimental and stochastic models of melanoma T-cell therapy define impact of subclone fitness on selection of antigen loss variants

Glodde

Kraut

et al. 2019

Preprint

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Antigen loss is a key mechanism how tumor cells escape from T-cell immunotherapy. Using a mouse model of melanoma we directly compared antigen downregulation by phenotypic adaptation with genetically hardwired antigen loss. Unexpectedly, genetic ablation of Pmel, the melanocyte differentiation antigen targeted by adoptively transferred CD8 + T-cells, impaired melanoma cell growth in untreated tumors due to competitive pressure exerted by the bulk wild-type population.This established an evolutionary scenario, where T-cell immunotherapy imposed a dynamic fitness switch on wild-type melanoma cells and antigen loss variants, which resulted in highly variable enrichment of the latter in recurrent tumors. Stochastic simulations by an individual-based continuous-time Markov process suggested variable fitness of subclones within the antigen loss variant population as the most likely cause, which was validated experimentally. In summary, we provide a framework to better understand how subclone heterogeneity in tumors influences immune selection of genetic antigen loss variants through stochastic events.

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Loss of p14 diminishes immunogenicity in melanoma via non‐canonical Wnt signaling by reducing the peptide surface density

Wohlfarth,

Kosnopfel,

Faber

et al. 2024

Molecular Oncology

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Immunotherapy has achieved tremendous success in melanoma. However, only around 50% of advanced melanoma patients benefit from immunotherapy. Cyclin‐dependent kinase inhibitor 2A (CDKN2A), encoding the two tumor‐suppressor proteins p14ARF and p16INK4a, belongs to the most frequently inactivated gene loci in melanoma and leads to decreased T cell infiltration. While the role of p16INK4a has been extensively investigated, knowledge about p14ARF in melanoma is scarce. In this study, we elucidate the impact of reduced p14ARF expression on melanoma immunogenicity. Knockdown of p14ARF in melanoma cell lines diminished their recognition and killing by melanoma differentiation antigen (MDA)‐specific T cells. Resistance was caused by a reduction of the peptide surface density of presented MDAs. Immunopeptidomic analyses revealed that antigen presentation via human leukocyte antigen class I (HLA‐I) molecules was enhanced upon p14ARF downregulation in general, but absolute and relative expression of cognate peptides was decreased. However, this phenotype is associated with a favorable outcome for melanoma patients. Limiting Wnt5a signaling reverted this phenotype, suggesting an involvement of non‐canonical Wnt signaling. Taken together, our data indicate a new mechanism limiting MDA‐specific T cell responses by decreasing both absolute and relative MDA‐peptide presentation in melanoma.

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Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions

Cited by 210 publications

References 63 publications

Cancer immune escape: MHC expression in primary tumours versus metastases

Cancer immune escape: MHC expression in primary tumours versus metastases

Experimental and stochastic models of melanoma T-cell therapy define impact of subclone fitness on selection of antigen loss variants

Loss of p14 diminishes immunogenicity in melanoma via non‐canonical Wnt signaling by reducing the peptide surface density

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