Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy in Melanoma

Author:

Romano Gabriele123ORCID,Paradiso Francesca45ORCID,Li Peng3ORCID,Shukla Pooja3ORCID,Barger Lindsay N.1ORCID,El Naggar Olivia1ORCID,Miller John P.6ORCID,Liang Roger J.3ORCID,Helms Timothy L.3ORCID,Lazar Alexander J.67ORCID,Wargo Jennifer A.8ORCID,Taraballi Francesca4ORCID,Costello James C.9ORCID,Kwong Lawrence N.3ORCID

Affiliation:

1. 1Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.

2. 2Immune Cell Regulation & Targeting Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

3. 3Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.

4. 4Center for Musculoskeletal Regeneration, Department of Orthopedics & Sports Medicine, Houston Methodist Research Institute, Houston, Texas.

5. 5Reproductive Biology and Gynecological Oncology Group, Swansea University Medical School, Swansea, United Kingdom.

6. 6Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas.

7. 7Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.

8. 8Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

9. 9Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Abstract

Abstract Patients with BRAF-mutant melanoma show substantial responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically “cold” after MRD establishment. Computational analysis identified candidate T-cell recruiting chemokines as strongly upregulated initially and steeply decreasing as the immune response faded. Therefore, we hypothesized that sustaining chemokine signaling could impair MRD maintenance through increased recruitment of effector T cells. We found that intratumoral administration of recombinant Cxcl9 (rCxcl9), either naked or loaded in microparticles, significantly impaired MRD relapse in BRAF-inhibited tumors, including several complete pathologic responses after microparticle-delivered rCxcl9 combined with BRAF and MEK inhibition. Our experiments constitute proof of concept that chemokine-based microparticle delivery systems are a potential strategy to forestall tumor relapse and thus improve the clinical success of first-line treatment methods.

Funder

National Cancer Institute

National Human Genome Research Institute

Melanoma Research Foundation

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Immunology

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