# Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2024 · $423,402

## Abstract

NK cells are the first line of defense against tumor cells. We recently developed CAR NK cells for the treatment of
multiple myeloma (MM), which demonstrates improved anti-MM activity. However, challenges still exist for NK cell-
based cancer immunotherapy: some tumor cells are resistant to cytotoxicity of NK cells that have a short life span
after infusion into patients. Thus, further understanding of NK cells will be critical to better harness this population
for immunotherapy. Our data recently published in Nature Immunology show that an important transcription factor,
XBP1s, encoded by an unconventionally spliced mRNA of X-box binding protein (XBP1), positively regulates NK
cell survival and effector functions. XBP1s regulates NK cell cytotoxicity and GZMB gene expression via direct
promoter binding. XBP1s physically interacts with T-BET, a master regulator in NK cells, suggesting that XBP1s
can recruit T-BET to the promoters of target genes. This discovery fills a current gap in the field, as T-BET is known
to positively regulate the expression of GZMB despite lacking direct T-BET binding sites on the GZMB promoter.
Moreover, IL-15, one of the most important cytokines regulating NK cell survival, development, and effector
functions, activates AKT signaling to increase stability of XBP1s protein via deubiquitination, leading to XBP1s
nuclear accumulation. Consistent with these human data, conditional knockout of Xbp1 in mice shows a decreased
number of NK cells and impaired NK cell anti-tumor activity. We believe that we have identified a novel IL-15-AKT-
XBP1s signaling pathway that plays key roles in regulating multiple aspects of NK cell biology. Thus, our overall
hypothesis is that this IL-15-AKT-XBP1s signaling pathway newly identified by our group positively
regulates NK cell survival and effector functions and can be utilized to improve NK cell or CAR NK cell-
based cancer immunotherapy. We propose mechanistic studies regarding how XBP1s regulates NK cell survival
and effector functions. We also propose combinational therapies of IL-15/IL-15Rα with CS1-CAR NK cells or with
B-I09, a novel drug targeting XBP1 splicing to XBP1s that has strong activity in treating various cancers including
MM. IL-15/IL-15Rα can selectively stabilize the XBP1s protein and prevent B-I09-mediated downregulation of
XBP1s and the associated inhibition of functions in NK cells. We will engineer CS1-CAR NK cells to express IL-
15/IL-15Rα or XBP1s to have enhanced in vivo persistence of these cells for continuous tumor eradication. Three
Aims are proposed. Aim 1: Study the mechanism and functional consequences of enhanced XBP1s protein
expression levels via IL-15-AKT signaling in NK cells. Aim 2: Study whether and/or how XBP1s regulates NK cell
survival, proliferation, and trafficking. Aim 3: Study the role of XBP1s in combination therapies of IL-15/IL-15Rα
with a novel drug targeting XPB1s, B-I09, and/or with CS1-CAR NK cells for the treatment of MM. Our project...

## Key facts

- **NIH application ID:** 10737627
- **Project number:** 5R01CA247550-05
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Jianhua Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,402
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-04-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10737627

## Citation

> US National Institutes of Health, RePORTER application 10737627, Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells (5R01CA247550-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10737627. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*