Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC

Cancer Discovery, 2022

Abstract

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, NFκB-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 S100a8/9hi 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.

The following products manufactured by our partner Bio X Cell are featured in this study:

• InVivoMab rat IgG2b isotype control, Clone: [LTF-2], Rat, Monoclonal, BXC-BE0090
• InVivoPlus anti-mouse CD4, Clone: [GK1.5], Rat, Monoclonal, BXC-BP0003-1
• InVivoMab anti-mouse CD8alpha, Clone: [2.43], Rat, Monoclonal, BXC-BE0061
• InVivoMab rat IgG2a isotype control, Clone: [2A3], Rat, Monoclonal (clone 2A3), BXC-BE0089
• InVivoMab anti-mouse Ly6G, Clone: [1A8], Rat, Monoclonal, BXC-BE0075-1