Journal
CANCER DISCOVERY
Volume 12, Issue 1, Pages 47-61Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-21-0369
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Funding
- NYU-Perlmutter Cancer Center Support Grant [P30CA016087]
- NCI/NIH [P01CA229086, R01CA252239.]
- NIH [CA49152, CA248896, P30 CA016087]
- [S10 OD021747]
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Our study suggests that inhibiting the SHP2/RAS/ERK pathway leads to upregulation of CXCR2 ligands and recruitment of S100A8 hi gMDSCs, suppressing T cells in non-small cell lung cancer. Combining SHP2/CXCR2 inhibitors can block gMDSC immigration, enhance Th1 polarization, induce highly cytotoxic CD8 + KLRG1 + effector T cells, and improve survival.
SHP2 inhibitors (SHP2i) alone and in various combinations are being tested in multiple tumors with overactivation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages, induced tumor-intrinsic CCL5/ CXCL10 secretion, and promoted B and T lymphocyte infiltration in Kras - and Egfr-mutant non- small cell lung cancer (NSCLC). However, treatment also increased intratumor granulocytic myeloid-derived suppressor cells (gMDSC) via tumor-intrinsic, NF Kappa B -dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRAS G12C inhibitor trials. Combined SHP2 (SHP099)/CXCR1/2 (SX682) inhibition depleted a specific cluster of S100a8/9hi gMDSCs, generated Klrg1+CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras- and Egfr -mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in patients with NSCLC. SIGNIFICANCE: Our study shows that inhibiting the SHP2/RAS/ERK pathway triggers NF Kappa B-dependent upregulation of CXCR2 ligands and recruitment of S100A8 hi gMDSCs, which suppress T cells. Combining SHP2/CXCR2 inhibitors blocks gMDSC immigration, resulting in enhanced Th1 polarization, induced CD8 +KLRG1+ effector T cells with high cytotoxic activity, and improved survival in multiple NSCLC models.
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