KIR2DS4 preferentially enhances the adaptive memory-like NK subset through NKG7 and IL15 in cytomegalovirus seropositive glioblastoma patients with improved survival outcome — ASN Events
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  2. Poster Session Two
  3. KIR2DS4 preferentially enhances the adaptive memory-like NK subset through NKG7 and IL15 in cytomegalovirus seropositive glioblastoma patients with improved survival outcome

KIR2DS4 preferentially enhances the adaptive memory-like NK subset through NKG7 and IL15 in cytomegalovirus seropositive glioblastoma patients with improved survival outcome (#216)

Mohummad Aminur Rahman 1 , Surendra Kumar 2 , Victoria S Anderson 1 , Kazi A Alam 1 , Gro Njølstad 3 , Timothy Holmes 1 , Stian Knappskog 3 4 , Martha Chekenya 1
  1. University of Bergen, Bergen, HORDALAND, Norway
  2. Memoruial University of Newfoundland, Canada
  3. Haukeland University , Bergen
  4. University of Bergen, Bergen

Glioblastoma (GBM) has a poor prognosis and resists molecular immunotherapy due to an immunologically inert microenvironment that evades T-cell responses. 80% of patients are cytomegalovirus (CMV) seropositive, potentially contributing to T-cell suppression. We found that NK cells from CMV seropositive patients with the KIR2DS4*00101 allele and HLA-C1/C2 ligands were highly activated and co-expressed NKG2C, associated with long-lived memory-like NK-cells. It remains unclear if these NKG2C+KIR2DS4+ NK-cells are adaptive memory subsets or how KIR2DS4 influences their phenotype. We hypothesize that these cells in GBM patients may represent adaptive memory NK-subsets affecting survival. Cox regression assessed the impact of KIR2DS4 and CMV on NKG2C+KIR2DS4+ NK-cells and survival in 108 GBM patients. Flow cytometry and RNA sequencing analyzed NK-cell phenotypes and gene expression in PBMCs and tumor-infiltrating immune cells. A sub-cohort of 33 GBM patients (22 CMV+, 11 CMV-) and 20 healthy donors (10 CMV+, 10 CMV-) were studied for adaptive memory NK-cell phenotypes. Post CMV infection, GBM patient’s NK-cells in peripheral blood were more differentiated with larger fractions of CD56dimCD57+NKG2C+ NK-subsets compared to healthy donors. These NK cells exhibited an adaptive-memory phenotype with reduced PLZF, FcεRγ, and NKp30. The PLZF⁻FcεRγ⁻ population was enriched in NKG2C⁺ subsets, confirming KIR2DS4⁺NKG2C⁺ NK-cells as memory-like. This CMV+KIR2DS4+NKG2C+ NK-cell subset was distinguished from CMV-KIR2DS4-NKG2C- conventional and CMV+NKG2C+ NK-cells, where NKG7, CXCL16 and IL15 genes associated with NK-cell activation, differentiation, and cytotoxicity were selectively expressed in tumor and not in healthy donors.  52 % of GBM patients with the KIR2DS4*00101 allele in context of CMV and KIR2DS4⁺NKG2C⁺ NK-cells had longer median survival of 15 months compared to 10.9 months in KIR2DS4- (HR 1.38, 95% CI [0.88–2.16]). Sequence and structural analysis revealed KIR2DS4 prefers and recognizes CMV peptides, potentially driving adaptive memory NK-cells in CMV+ GBM patients. Targeting these mechanisms could enable new immunotherapy strategies for GBM.