Divergent clinical and immunologic outcomes based on STK11 Co-mutation status in resectable KRAS-mutant lung cancers following neoadjuvant immune checkpoint blockade Journal Article

   

Authors:	Rosner, S.; Connor, S.; Sanber, K.; Zahurak, M.; Zhang, T.; Gurumurthy, I.; Zeng, Z.; Presson, B.; Singh, D.; Rayes, R.; Sivapalan, L.; Pereira, G.; Ji, Z.; Thummalapalli, R.; Reuss, J. E.; Broderick, S. R.; Jones, D. R.; Deutsch, J. S.; Cottrell, T. R.; Chaft, J. E.; Spicer, J.; Taube, J.; Anagnostou, V.; Brahmer, J. R.; Pardoll, D. M.; Ji, H.; Forde, P. M.; Marrone, K. A.; Smith, K. N.
Article Title:	Divergent clinical and immunologic outcomes based on STK11 Co-mutation status in resectable KRAS-mutant lung cancers following neoadjuvant immune checkpoint blockade
Abstract:	Purpose: Co-mutations of the Kirsten rat sarcoma virus (KRAS) and serine/threonine kinase 11 (STK11) genes in advanced non-small cell lung cancer (NSCLC) are associated with immune checkpoint blockade (ICB) resistance. Although neoadjuvant chemoimmunotherapy is now a standard-of-care treatment for resectable NSCLC, the clinical and immunologic impacts of KRAS and STK11 co-mutations in this setting are unknown. Experimental Design: We evaluated and compared recurrencefree survival of resectable KRAS-mutated NSCLC tumors, with or without co-occurring STK11 mutations, treated with neoadjuvant ICB. Single-cell transcriptomics was performed on tumorinfiltrating T cells from seven KRASmut/STK11wt tumors and six KRAS and STK11 co-mutated (KRASmut/STK11mut) tumors. Results: Relative to KRASmut/STK11wt tumors, KRASmut/ STK11mut exhibited significantly higher recurrence risk. Singlecell transcriptomics showed enhanced oxidative phosphorylation with evidence of decreased prostaglandin E2 signaling and increased IL-2 signaling in CD8+ tumor-infiltrating lymphocytes (TIL) from KRASmut/STK11mut tumors, a finding that was mirrored in KRASwt tumors that relapsed. TILs from KRASmut/ STK11mut tumors expressed high levels of molecules associated with tumor residence, including CD39 and ZNF683 (HOBIT). Conclusions: These divergent T-cell transcriptional fates suggest that T-cell maintenance and residence may be detrimental to antitumor immunity in the context of neoadjuvant ICB for resectable NSCLC, regardless of KRAS mutation status. Our work provides a basis for future investigations into the mechanisms underpinning prostaglandin E2 signaling and IL-2 signaling as they relate to T-cell immunity to cancer and to divergent clinical outcomes in KRASmut/ STK11mut NSCLC treated with neoadjuvant ICB. © 2024 The Authors.
Keywords:	adult; human tissue; aged; middle aged; excision; gene mutation; major clinical study; overall survival; sequence analysis; genetics; mutation; clinical feature; paclitaxel; neoadjuvant therapy; outcome assessment; recurrence risk; cd8+ t lymphocyte; t lymphocyte; tumor associated leukocyte; lymphocytes, tumor-infiltrating; phenotype; metabolism; carboplatin; interleukin 2; ipilimumab; gene expression; gene expression profiling; carcinoma, non-small-cell lung; lung neoplasms; cohort analysis; lung cancer; cytotoxicity; pathology; protein serine threonine kinase; retrospective study; transcriptomics; protein p53; histology; lung tumor; immunology; cellular immunity; multicenter study; prostaglandin e2; drug therapy; k ras protein; protein p21; proto-oncogene proteins p21(ras); oxidative phosphorylation; kras protein, human; rna sequence; recurrence free survival; non small cell lung cancer; principal component analysis; clinical outcome; exploratory research; protein kinase lkb1; stk11 protein, human; procedures; immune checkpoint inhibitor; mitophagy; nivolumab; humans; human; male; female; article; differential expression analysis; immune checkpoint inhibitors; protein serine-threonine kinases; checkpoint inhibitor therapy; amp-activated protein kinase kinases; hydroxymethylglutaryl coenzyme a reductase kinase kinase
Journal Title:	Clinical Cancer Research
Volume:	31
Issue:	2
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2025-01-15
Start Page:	339
End Page:	351
Language:	English
DOI:	10.1158/1078-0432.Ccr-24-2983
PUBMED:	39545922
PROVIDER:	scopus
PMCID:	PMC11739779
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85215219756&doi=10.1158%2f1078-0432.CCR-24-2983&partnerID=40&md5=402df151ed32f8d586dccdba4fd2df1f
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/222155