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