{"doi":"10.1101/2021.03.21.436338","title":"Combined Inhibition of SHP2 and CXCR1/2 Promotes Anti-Tumor T Cell Response in NSCLC","abstract":"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 KRAS G12C -inhibitor trials. Combined SHP2(SHP099)/CXCR1/2(SX682) inhibition depleted a specific cluster of S100a8/9 high 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 S100A8 high 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":213761,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":428517,"name":"Shuai Li","orcid":"0000-0002-3492-7176","position":1,"is_corresponding":false},{"id":259273,"name":"Alireza Khodadadi‐Jamayran","orcid":"0000-0003-2495-7504","position":2,"is_corresponding":false},{"id":556133,"name":"Jayu Jen","orcid":"0000-0002-0926-9984","position":3,"is_corresponding":false},{"id":671026,"name":"Han Han","orcid":"0000-0002-1519-0842","position":4,"is_corresponding":false},{"id":806330,"name":"Kayla Guidry","orcid":"0000-0001-8190-0278","position":5,"is_corresponding":false},{"id":227601,"name":"Ting Chen","orcid":"0000-0003-1725-7956","position":6,"is_corresponding":false},{"id":75631,"name":"Yuan Hao","orcid":"0000-0002-1588-0587","position":7,"is_corresponding":false},{"id":238051,"name":"Carmine Fedele","orcid":"0000-0002-9196-0896","position":8,"is_corresponding":false},{"id":284011,"name":"John A. Zebala","orcid":"0000-0002-3581-6750","position":9,"is_corresponding":false},{"id":284010,"name":"Dean Y. Maeda","orcid":"0000-0002-9304-6846","position":10,"is_corresponding":false},{"id":615203,"name":"James G. Christensen","orcid":"0000-0003-1835-0335","position":11,"is_corresponding":false},{"id":615197,"name":"Peter Olson","orcid":"0009-0008-5164-8102","position":12,"is_corresponding":false},{"id":379039,"name":"Argus Athanas","orcid":"0000-0001-7293-0096","position":13,"is_corresponding":false},{"id":20939,"name":"Kwok‐Kin Wong","orcid":"0000-0001-6323-235X","position":14,"is_corresponding":false},{"id":238068,"name":"Benjamin G. Neel","orcid":"0000-0002-9589-585X","position":15,"is_corresponding":false},{"id":238061,"name":"Kwan Ho Tang","orcid":"0000-0001-7729-5159","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T23:52:41.672172Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}