# Intratumoral plasma cells in MPNST response to CDK4/6 targeted therapy and sensitization to immune checkpoint blockade

> **NIH NIH F31** · UNIVERSITY OF IOWA · 2024 · $34,667

## Abstract

Project Summary / Abstract
Malignant peripheral nerve sheath tumors (MPSNTs) are deadly, essentially incurable sarcomas that lack
effective therapies. Hallmark alterations driving MPNSTs are NF1 mutation, leading to Ras-MEK activation,
and loss of CDKN2A, leading to hyperactivation of CDK4/6. Our lab found that dual inhibition of MEK and
CDK4/6 (simplified as ‘CDK4/6 targeted therapy’ since both drugs downregulate CDK4/6) acts synergistically
to dramatically shrink de novo MPNSTs in immune competent mice. Tumor regression coincides with an
increase in intratumoral plasma cells (IPCs), which was not observed in vehicle control and drug-resistant
tumors. IPCs prognose better overall survival, increased formation of tertiary lymphoid structures (TLS)
containing activated CD8+ T cells, and improved response to immune checkpoint blockade (ICB) therapies in
many human cancers, including other sarcomas. I found that CDK4/6 targeted therapy sensitizes de novo
MPNSTs to ICB using Programmed Death Ligand 1 (PD-L1) antibodies with the combination achieving
apparent cure in 10% of mice. These findings support my central hypothesis that CDK4/6 targeted therapy
causes tumor regression and enhanced response to ICB therapy through a plasma-cell dependent modulation
of tumor infiltrating immune cells. This will be tested through two complementary aims:
Aim 1: Define IPC associations with immune composition changes in MPNSTs caused by CDK4/6 targeted
 therapy with or without anti-PDL1 therapy.
Aim 2: Determine the mechanism and significance of IPCs in the MPNST immune response to CDK4/6
 targeted and/or anti-PDL1 therapy.
Proposed studies employ an established model of de novo MPNSTs generated by CRISPR editing of
Nf1+Cdkn2a in immune competent mice, closely mimicking the human disease. Changes in the immune
composition of MPNSTs following therapy will be determined through histopathological, flow cytometric,
cytokine/chemokine arrays and transcriptome analyses and results correlated with the antitumor efficacy of the
therapies. Through these aims, I will elucidate therapy-induced changes in IPCs and other tumor infiltrating
immune cells and determine if plasma cell loss reduces the antitumor efficacy of CDK4/6 targeted and/or ICB
therapy. Such experiments will, for the first time in any tumor type, establish the significance of therapy-
induced IPCs in the antitumor immune response. The role of IPCs in potentiating kinase inhibitor and ICB
therapies is of growing interest but so far remains untested; it will be defined here in the setting of MPNSTs.
Findings may guide new treatments for MPNSTs, including immunotherapy involving ICB agents, and have
broad applicability to other cancers.

## Key facts

- **NIH application ID:** 10869912
- **Project number:** 5F31CA281312-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Joshua J Lingo
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,667
- **Award type:** 5
- **Project period:** 2023-06-01 → 2025-05-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869912

## Citation

> US National Institutes of Health, RePORTER application 10869912, Intratumoral plasma cells in MPNST response to CDK4/6 targeted therapy and sensitization to immune checkpoint blockade (5F31CA281312-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10869912. Licensed CC0.

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