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. 2024 Oct 22;8(20):5365-5370.
doi: 10.1182/bloodadvances.2023010869.

Inhibition of MICA and MICB shedding enhances memory-like NK-cell-mediated cytotoxicity against multiple myeloma

Sabrin Tahri  1   2   3   4   5 , Sara Piccinelli  1   2 , Nang Kham Su  1   2   3   4 , Luisa Lampe  1   2   3   4   6 , Han Dong  1 , Juliana Vergara Cadavid  1 , Rebecca Boiarsky  3   7 , Natalie Papazian  5 , Elizabeth D Lightbody  1   2   3   4 , Amanda Cao  1   2 , Jean-Baptiste Alberge  1   2   3   4 , Lucas Ferrari de Andrade  8 , Mahshid Rahmat  1   2   3   4 , Yujia Shen  1   9   10 , Laura Blanco Fernández  11 , Aintzane Zabaleta  11 , Andreas Günther  6 , Gad Getz  3   12   13 , Pieter Sonneveld  5 , Tom Cupedo  5 , Kai W Wucherpfennig  14 , Irene M Ghobrial  1   2   3   4 , Rizwan Romee  1   2
Affiliations

Inhibition of MICA and MICB shedding enhances memory-like NK-cell-mediated cytotoxicity against multiple myeloma

Sabrin Tahri et al. Blood Adv. .
No abstract available

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Conflict of interest statement

Conflict-of-interest disclosure: I.M.G. has acted as a consultant for Bristol Myers Squibb, Novartis, Amgen, Takeda, Noxxon Pharmaceuticals, Celgene, Sanofi, Genentech, GlaxoSmithKline, Gene Network Sciences Healthcare, Karyopharm Therapeutics, Adaptive Biotechnologies, Janssen, Medscape, and AbbVie, and has received honoraria from Celgene, Bristol Myers Squibb, Takeda, Amgen, Janssen, Karyopharm Therapeutics, Cellectar Biosciences, Adaptive Biotechnologies, Sanofi, and Medscape. P.S. reports consulting fees and research support from Celgene, Janssen, Karyopharm Therapeutics, and SkylineDx. K.W.W. serves on the scientific advisory boards of SQZ Biotech, Nextech Invest, Bisou Bioscience, and TScan Therapeutics; receives sponsored research funding from Novartis; and is a scientific cofounder of Immunitas Therapeutics. R.R. receives sponsored research funding from CRISPR Therapeutics and Skyline Therapeutics; owns equity in InnDura Therapeutics; and serves on the scientific advisory board of Glycostem Therapeutics and XNK Therapeutics. L.F.d.A. is a coinventor on an issued patent for an α3 domain-specific antibody and has served as a consultant for Cullinan Oncology. The remaining authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Inhibition of MICA/B shedding enhances memory-like NK cell–mediated cytotoxicity against MM. (A) MICA, MICB, PDIA6 (ERp5), and ADAM10 gene expression levels in 1389 tumor cell lines from the Cancer Cell Line Encyclopedia database. Gene expression levels are presented as log2(transcripts per million [TPM] + 1). (B) MICA/B surface expression in 10 different HMCLs, as measured by flow cytometry. (C) MICA/B gene expression levels in 9 different HMCLs from the publicly available Broad CCLE data set. (D) Dose-dependent increase in MICA/B surface expression in HMCL MM.1S in response to 7C6 treatment. Significance was calculated using the t test. (E) Shed MICB was determined using sandwich enzyme-linked immunosorbent assay. A decrease in soluble MICB was seen in response to the 7C6 mAb treatment. For functional assays, effector cells (conventional or memory-like NK cells) were cocultured with MM.1S at a 5:1 effector-to-target ratio for 6 hours. (F) Increased CD107a degranulation (n = 7), IFN-γ production (n = 10), and tumor necrosis factor-α (TNF-α) production (n = 7) measured by flow cytometry in response to 7C6 treatment of cNK cells. (G) Summary of cytotoxicity (n = 9) of cNK and memory-like NK cells upon 7C6 mAb treatment of MM.1S cells. Data are depicted as the mean ± standard deviation. Significance was calculated using the Wilcoxon test for comparison of IC and 7C6 treatment conditions, and the Mann-Whitney U test was used for the remainder of the comparisons; ns, P > .05; ∗P ≤ .05; ∗∗P ≤ .01; ∗∗∗P ≤ .001; ∗∗∗∗P ≤ .0001. E:T, effector:target; IC, isotype control; ns, not significant.
Figure 2.
Figure 2.
Combined MICA/B stabilization and memory-like NK cell transfer leads to early tumor control in vivo. (A) Experimental design. (B) Representative bioluminescence imaging (BLI) of recipient mice 9 and 12 days after engraftment with MM.1S-luc. Note the scale bar with lower intensities for the BLI signal in the 7C6-treated mice. (C) Enumeration of serial BLI measurements that show reduced tumor burden in mice receiving 7C6 mAb treatment compared with the isotype control. Differences were determined using the Mann-Whitney test; ns, P > .05; ∗P ≤ .05; ∗∗P ≤ .01; ∗∗∗P ≤ .001; ∗∗∗∗P ≤ .0001. IC, isotype control; ns, not significant.
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References

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