Katja Harbst

Lund University

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Transcriptomic landscape of tumour cells undergoing T-cell attack

Annals of Oncology (2019)

Aishwarya Gokuldass Aimilia Schina Martin Lauss Katja Harbst Christopher A. Chamberlain

10.1093/annonc/mdz447.028

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Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFNγ Signaling

Cancer Research (2017)

Marco Donia Katja Harbst Marit van Buuren Pia Kvistborg Mattias F. Lindberg

Abstract Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell–based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNγ signaling, led to impaired recognition by tumor-specific CD8+ T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I–related APM. Loss of target antigens or impaired IFNγ signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted. Cancer Res; 77(17); 4562–6. ©2017 AACR.

Cancer Immunotherapy

10.1158/0008-5472.can-16-3172

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Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2mutation carriers

Breast Cancer Research (2012)

Antonis C. Antoniou Karoline Kuchenbaecker Penny Soucy Jonathan Beesley Xiaohong Chen

Abstract Introduction Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B) , rs10995190 ( ZNF365) , rs704010 ( ZMIZ1 ), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P -trend = 3 × 10 -4 ). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P -trend = 3.1 × 10 -5 , P -difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P -trend = 0.015; rs1011970, P -trend = 0.048; rs865686, 2df- P = 0.007; rs1292011 2df- P = 0.03. rs10771399 ( PTHLH ) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P -trend = 4 × 10 -5 ) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P -trend = 0.049). Conclusions The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

10.1186/bcr3121

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The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma

Cell Reports (2019)

Bengt Phung Maciej Cieśla Adriana Sanna Nicola Guzzi Giulia Beneventi

Highlights•DDX3X is frequently altered in human metastatic melanomas•Loss of DDX3X impacts translation capacity and phenotype of melanoma cells•DDX3X directs MITF oncogene translation through an IRES element located in its mRNA•Altered MITF translational regulation drives melanoma metastasis and therapy resistanceSummaryThe X-linked DDX3X gene encodes an ATP-dependent DEAD-box RNA helicase frequently altered in various human cancers, including melanomas. Despite its important roles in translation and splicing, how DDX3X dysfunction specifically rewires gene expression in melanoma remains completely unknown. Here, we uncover a DDX3X-driven post-transcriptional program that dictates melanoma phenotype and poor disease prognosis. Through an unbiased analysis of translating ribosomes, we identified the microphthalmia-associated transcription factor, MITF, as a key DDX3X translational target that directs a proliferative-to-metastatic phenotypic switch in melanoma cells. Mechanistically, DDX3X controls MITF mRNA translation via an internal ribosome entry site (IRES) embedded within the 5′ UTR. Through this exquisite translation-based regulatory mechanism, DDX3X steers MITF protein levels dictating melanoma metastatic potential in vivo and response to targeted therapy. Together, these findings unravel a post-transcriptional layer of gene regulation that may provide a unique therapeutic vulnerability in aggressive male melanomas.Graphical abstract

Reprogramming

RNA Helicase A

10.1016/j.celrep.2019.05.069

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Citations (69)

762 A combination of functional biomarkers improves identification of the tumor-specific reactive T cell repertoire

Arianna Draghi Katja Harbst Inge Marie Svane Marco Donia

Background

Detecting the entire repertoire of tumor-specific reactive T cells is essential for investigating the broad range of T cell functions in the tumor-microenvironment. At present, assays identifying tumor-specific functional activation measure either upregulation of specific surface molecules, de novo production of the most common antitumor cytokines or mobilization of cytotoxic granules.

Methods

In this study, we combined transcriptomic analyses of tumor-specific reactive tumorinfiltrating lymphocytes (TILs), TIL-autologous tumor cell co-cultures and commonly used established detection protocols to develop an intracellular flow cytometry staining method encompassing simultaneous detection of intracellular CD137, de novo production of TNF and IFNy and extracellular mobilization of CD107a.

Results

This approach enabled the identification of a larger fraction of tumor-specific reactive T cells in vitro compared to standard methods, revealing the existence of multiple distinct functional clusters of tumor-specific reactive TILs. Publicly available datasets of fresh tumor single-cell RNA-sequencing from four cancer types were investigated to confirm that these functional biomarkers identified distinct functional clusters forming the entire repertoire of tumor-specific reactive T cells in situ.

Conclusions

In conclusion, we describe a simple method using a combination of functional biomarkers that improves identification of the tumor-specific reactive T cell repertoire in vitro and in situ.

CD137

10.1136/jitc-2020-sitc2020.0762

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A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population

Nature Genetics (2010)

Antonis C. Antoniou Xianshu Wang Zachary S Fredericksen Lesley McGuffog Robert F. Tarrell

Genome-wide Association Study

10.1038/ng.669

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Citations (332)

Supplementary Figure S1-S5 from Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFNγ Signaling