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SHP-2 and PD-L1 Inhibition Combined with Radiotherapy Enhances Systemic Antitumor Effects in an Anti–PD-1–Resistant Model of Non–Small Cell Lung Cancer
Open accessPublished version of a preprint
Abstract
Immune checkpoint inhibitors, such as anti–PD-1/PD-L1, have emerged as promising therapies for advanced non–small cell lung cancer (NSCLC). However, approximately 80% of patients do not respond to immunotherapy given alone because of intrinsic or acquired resistance. Radiotherapy (XRT) can overcome PD-1 resistance and improve treatment outcomes, but its efficacy remains suboptimal. The tyrosine phosphatase SHP-2, expressed in some cancers and in immune cells, has been shown to negatively affect antitumor immunity. Our hypothesis was that SHP-2 inhibition in combination with anti–PD-L1 would enhance immune-mediated responses to XRT and synergistically boost antitumor effects in an anti–PD-1–resistant mouse model. We treated 129Sv/Ev mice with anti–PD-1–resistant 344SQ NSCLC adenocarcinoma with oral SHP099 (a SHP-2 inhibitor) combined with XRT and intraperitoneal anti–PD-L1. Primary tumors were treated with XRT (three fractions of 12 Gy each), whereas abscopal (out-of-field) tumors were observed but not treated. XRT in combination with SHP099 and anti–PD-L1 promoted local and abscopal responses, reduced lung metastases, and improved mouse survival. XRT also increased SHP-2+ M1 tumor-associated macrophages in abscopal tumors (P = 0.019). The addition of SHP099 also associated with a higher M1/M2 ratio, greater numbers of CD8+ T cells, and fewer regulatory T cells. This triple-combination therapy had strong antitumor effects in a mouse model of anti–PD-1–resistant NSCLC and may be a novel therapeutic approach for anti–PD-1–resistant NSCLC in patients.
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“SHP2 inhibitor enhanced the efficacy of α-PD-1 in murine tumor models [252–254].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [253]
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Metadata
- Authors
- Chen, D., Barsoumian, H. B., Yang, L., Younes, A. I., Verma, V., Hu, Y., Menon, H., Wasley, M., Masropour, F., Mosaffa, S., Ozgen, T., Klein, K., Cortez, M. A., & Welsh, J. W.
- Affiliations
- Shandong University (CN)
- The University of Texas MD Anderson Cancer Center (US)
- Allegheny General Hospital (US)
- The University of Texas at Austin (US)
- 2Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- ORCID
- Venue
- Cancer Immunology Research
- Published
- 2020-07-01
- Volume
- 8
- Issue
- 7
- Pages
- 883-894
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC10173258
- OpenAlex
- W3016731543
- Cited by
- 107
- References
- 38
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 40 · 2023: 14 · 2022: 19 · 2021: 13 · 2020: 2
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NCI NIH (P30 CA016672)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- SHP2, SHP099, PD-L1 blockade, anti-PD-1 resistance, non-small cell lung cancer, radiotherapy, immune checkpoint inhibitors, abscopal effect, tumor-associated macrophages, macrophage polarization, CD8+ T cells, regulatory T cells, lung metastasis, combination immunotherapy
- MeSH terms
- Antineoplastic Agents, Immunological, Animals, Carcinoma, Non-Small-Cell Lung, Female, Lung Neoplasms, Mice, Inbred C57BL, Piperidines, Pyrimidines, Drug Resistance, Neoplasm, Cell Line, Tumor, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Mice, 129 Strain, Chemoradiotherapy, B7-H1 Antigen
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