KIR2DS1–HLA-C status as a predictive marker for benefit from rituximab: a post-hoc analysis of the RICOVER-60 and CLL8 trials

Kaddu‐Mulindwa, Dominic; Altmann, Bettina; Robrecht, Sandra; Ziepert, Marita; Regitz, Evi; Tausch, Eugen; Held, Gerhard; Poeschel, Viola; Lesan, Vadim; Bittenbring, Joerg Thomas; Thurner, Lorenz; Pfreundschuh, Michael; Christofyllakis, Konstantinos; Truemper, Lorenz; Loeffler, Markus; Schmitz, Norbert; Hoth, Markus; Hallek, Michael; Fischer, Kirsten; Stilgenbauer, Stephan; Bewarder, Moritz; Rixecker, Torben

doi:10.1016/s2352-3026(21)00369-0

Cited by 6 publications

(3 citation statements)

References 30 publications

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“…Assessment of the HLA genotype might aid in identifying patients with higher risk of immunity-mediated AKI, who would possibly show better response to steroid or immunosuppressive therapy. 68 Because specific T-cell subset-relevant cytokine IL9 and TNF- α have been shown to be helpful in ATIN diagnosis and prognosis, 11,12 future inclusion of HLA genotype may further improve precise understanding of the disease mechanism, guide management decisions, and help enroll appropriate patients in therapeutic trials.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study in Acute Tubulointerstitial Nephritis

Zhou

Xie

et al. 2023

JASN

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Background Acute tubulointerstitial nephritis (ATIN) is a rare immune-related disease, accounting for approximately 10% of patients with unexplained AKI. Previous elucidation of the relationship between genetic factors that contribute to its pathogenesis was hampered because of small sample sizes and candidate gene design.Methods We undertook the first two-stage genome-wide association study and meta-analysis involving 544 kidney biopsy-defined patients with ATIN and 2346 controls of Chinese ancestry. We conducted statistical fine-mapping analysis, provided functional annotations of significant variants, estimated single nucleotide polymorphism (SNP)-based heritability, and checked genotype and subphenotype correlations.Results Two genome-wide significant loci, rs35087390 of HLA-DQA1 (P53.01310 239 ) on 6p21.32 and rs2417771 of PLEKHA5 on 12p12.3 (P52.14310 28 ), emerged from the analysis. HLA imputation using two reference panels suggested that HLA-DRB1*14 mainly drives the HLA risk association. HLA-DRB1 residue 60 belonging to pocket P10 was the key amino acid position. The SNP-based heritability estimates with and without the HLA locus were 20.43% and 10.35%, respectively. Different clinical subphenotypes (drug-related or tubulointerstitial nephritis and uveitis syndrome) seemed to share the same risk alleles. However, the HLA risk genotype was associated with disease severity and response rate to immunosuppressive therapy. ConclusionsWe identified two candidate genome regions associated with susceptibility to ATIN. The findings suggest that a genetically conferred risk of immune dysregulation is involved in the pathogenesis of ATIN.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study in Acute Tubulointerstitial Nephritis

Zhou

Xie

et al. 2023

JASN

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“…In a study of malignant neoplasms, the importance of the KIR-HLA-C variants was highlighted when applying chemotherapy treatments and drugs such as “rituximab”. It was shown that those HLA-C2 homozygotes did not benefit from the drug, while those with the KIR2DS1-HLA-C variant considerably increased their survival rate ( Kaddu-Mulindwa et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“HLA-C: evolution, epigenetics, and pathological implications in the major histocompatibility complex”

et al. 2023

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HLA-C, a gene located within the major histocompatibility complex, has emerged as a prominent target in biomedical research due to its involvement in various diseases, including cancer and autoimmune disorders; even though its recent addition to the MHC, the interaction between HLA-C and KIR is crucial for immune responses, particularly in viral infections. This review provides an overview of the structure, origin, function, and pathological implications of HLA-C in the major histocompatibility complex. In the last decade, we systematically reviewed original publications from Pubmed, ScienceDirect, Scopus, and Google Scholar. Our findings reveal that genetic variations in HLA-C can determine susceptibility or resistance to certain diseases. However, the first four exons of HLA-C are particularly susceptible to epigenetic modifications, which can lead to gene silencing and alterations in immune function. These alterations can manifest in diseases such as alopecia areata and psoriasis and can also impact susceptibility to cancer and the effectiveness of cancer treatments. By comprehending the intricate interplay between genetic and epigenetic factors that regulate HLA-C expression, researchers may develop novel strategies for preventing and treating diseases associated with HLA-C dysregulation.

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“…This has implications in hematopoietic cell transplantation, where HLA-matching is only beneficial in the absence of homozygous HLA-C2 ( 102 , 103 ). Moreover, for the treatment of B-cell malignancies, addition of rituximab to chemotherapy did not improve survival outcomes in patients with KIR2DS1-HLA-C2/C2 ( 104 ), suggesting that KIR2DS1 and HLA-C status could be a predictive marker for efficacy of rituximab due to the potential of hyporesponsive NK cells ( 104 ).…”

Section: Receptor Driven Signaling In Natural Killer Cellsmentioning

confidence: 99%

Killer instincts: natural killer cells as multifactorial cancer immunotherapy

Nersesian,

Carter,

Lee

et al. 2023

Front. Immunol.

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Natural killer (NK) cells integrate heterogeneous signals for activation and inhibition using germline-encoded receptors. These receptors are stochastically co-expressed, and their concurrent engagement and signaling can adjust the sensitivity of individual cells to putative targets. Against cancers, which mutate and evolve under therapeutic and immunologic pressure, the diversity for recognition provided by NK cells may be key to comprehensive cancer control. NK cells are already being trialled as adoptive cell therapy and targets for immunotherapeutic agents. However, strategies to leverage their naturally occurring diversity and agility have not yet been developed. In this review, we discuss the receptors and signaling pathways through which signals for activation or inhibition are generated in NK cells, focusing on their roles in cancer and potential as targets for immunotherapies. Finally, we consider the impacts of receptor co-expression and the potential to engage multiple pathways of NK cell reactivity to maximize the scope and strength of antitumor activities.

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KIR2DS1–HLA-C status as a predictive marker for benefit from rituximab: a post-hoc analysis of the RICOVER-60 and CLL8 trials

Cited by 6 publications

References 30 publications

Genome-Wide Association Study in Acute Tubulointerstitial Nephritis

Genome-Wide Association Study in Acute Tubulointerstitial Nephritis

“HLA-C: evolution, epigenetics, and pathological implications in the major histocompatibility complex”

Killer instincts: natural killer cells as multifactorial cancer immunotherapy

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