Divergent Clinical and Immunologic Outcomes Based on STK11 Co-mutation Status in Resectable KRAS-Mutant Lung Cancers Following Neoadjuvant Immune Checkpoint Blockade

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2024 Nov 15

PMID 39545922

Authors

Samuel Rosner

Sydney Connor

Khaled Sanber

Marianna Zahurak

Tianbei Zhang

Isha Gurumurthy

Zhen Zeng

Brad Presson

Dipika Singh

Roni Rayes

Lavanya Sivapalan

Gavin Pereira

Zhicheng Ji

Rohit Thummalapalli

Joshua E Reuss

Stephen R Broderick

David R Jones

Julie S Deutsch

Tricia R Cottrell

Jamie E Chaft

Jamie Chaft

Jonathan Spicer

Janis Taube

Valsamo Anagnostou

Julie R Brahmer

Drew M Pardoll

Hongkai Ji

Patrick M Forde

Kristen A Marrone

Kellie N Smith

Affiliations

Soon will be listed here.

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 recurrence-free survival of resectable KRAS-mutated NSCLC tumors, with or without co-occurring STK11 mutations, treated with neoadjuvant ICB. Single-cell transcriptomics was performed on tumor-infiltrating 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. Single-cell 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.

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