Abstract
Clinical trials of SHP2 inhibitors (SHP2i) alone and in various combinations are ongoing for multiple tumors with over-activation 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 and promoted B and T lymphocyte infiltration in Kras- and Egfr-mutant non-small cell lung cancer (NSCLC). However, treatment also increased intratumor gMDSCs via tumor-intrinsic, NF-kB-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 KRASG12C-inhibitor trials. Combined SHP2(SHP099)/CXCR1/2(SX682) inhibition depleted a specific cluster of S100a8/9high 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 NSCLC patients.
Statement of Significance Our study shows that inhibiting the SHP2/RAS/ERK pathway triggers NF-kB-dependent up-regulation of CXCR2 ligands and recruitment of S100A8high gMDSCs, which suppress T cells in NSCLC. Combining SHP2 and CXCR2 inhibitors blocks this gMDSC immigration, resulting in enhanced Th1 polarization, induction of CD8+ KLRG1+ effector T cells with high cytotoxic activity and improved survival in multiple NSCLC models.
Competing Interest Statement
J.Z. has equity in Syntrix. P.O. holds equity in Mirati Therapeutics. J.C. holds equity in Mirati Therapeutics. A.J.A. receives consulting fees from Mirati Therapeutics. K.K.W. is a founder of and equity holder in G1 Therapeutics. He also has sponsored Research Agreements with Takeda, BMS, Mirati, Merus, Alkermes, Ansun Biopharma, Tvardi Therapeutics, Delfi Diagnostics, and Dracen Pharmaceuticals and consulting agreements with AstraZeneca, Novartis, Merck, Recursion, Navire, Prelude and Ono. K.K.W Wong has consulting & sponsored research agreements with Janssen, Pfizer, and Zentalis. B.G.N. is a founder of, holds equity in, and receives consulting fees from Navire Pharm and Jengu Therapeutics, and is a founder of and holds equity in Northern Biologics, LP. He also receives consulting fees and equity from Arvinas, Inc., and holds equity in Recursion Pharma and received consulting fees from MPM Capital. His spouse holds equity in Amgen, Inc. and held equity in Moderna and Regeneron at times during this study. No disclosures were reported by the other authors.
Footnotes
Conflicts of Interest: J.Z. has equity in Syntrix. P.O. holds equity in Mirati Therapeutics. J.C. holds equity in Mirati Therapeutics. A.J.A. receives consulting fees from Mirati Therapeutics. K.K.W. is a founder of and equity holder in G1 Therapeutics. He also has sponsored Research Agreements with Takeda, BMS, Mirati, Merus, Alkermes, Ansun Biopharma, Tvardi Therapeutics, Delfi Diagnostics, and Dracen Pharmaceuticals and consulting agreements with AstraZeneca, Novartis, Merck, Recursion, Navire, Prelude and Ono. K.K.W Wong has consulting & sponsored research agreements with Janssen, Pfizer, and Zentalis. B.G.N. is a founder of, holds equity in, and receives consulting fees from Navire Pharm and Jengu Therapeutics, and is a founder of and holds equity in Northern Biologics, LP. He also receives consulting fees and equity from Arvinas, Inc., and holds equity in Recursion Pharma and received consulting fees from MPM Capital. His spouse holds equity in Amgen, Inc. and held equity in Moderna and Regeneron at times during this study. No disclosures were reported by the other authors.
