Purpose: Co-mutations of the KRAS and STK11 genes in advanced non-small cell lung cancer (NSCLC) are associated with immune checkpoint blockade (ICB) resistance. While neoadjuvant chemoimmunotherapy is now a standard of care treatment for resectable NSCLC, the clinical and immunologic impact of KRAS andSTK11 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-occuring STK11 mutations, treated with neoadjuvant ICB. Single cell transcriptomics was performed on tumor-infiltrating T cells from 7 KRASmut/STK11wttumors and 6 KRASmut/STK11mut tumors.
Results: Relative to KRASmut/STK11wttumors, KRASmut/STK11mut exhibited significantly higher recurrence risk. Single-cell transcriptomics showed enhanced oxidative phosphorylation with evidence of decreased PGE-2 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. TIL 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 T cell maintenance and residence may be detrimental to anti-tumor 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 PGE-2 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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http://dx.doi.org/10.1158/1078-0432.CCR-24-2983 | DOI Listing |
BMC Cancer
December 2024
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 430, Houston, Texas, 77030-4009, USA.
Eur J Cancer
January 2025
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands; Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; University Clinic Regensburg, Dept. Hematology and Medical Oncology, Regensburg, Germany. Electronic address:
Background: Pathologic response following neoadjuvant immune checkpoint blockade (ICB) in stage III melanoma serves as a surrogate marker for long-term outcomes. This may support more personalized, response-directed treatment strategies.
Methods: The OpACIN-neo and PRADO trials were phase 2 studies evaluating neoadjuvant treatment with ipilimumab and nivolumab in stage III melanoma.
Clin Cancer Res
November 2024
Johns Hopkins Medicine, Baltimore, MD, United States.
Cell Rep Med
November 2024
Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
Only a subset of patients with breast cancer responds to immune checkpoint blockade (ICB). To better understand the underlying mechanisms, we analyze pretreatment biopsies from patients in the I-SPY 2 trial who receive neoadjuvant ICB using multiple platforms to profile the tumor microenvironment. A variety of immune cell populations and markers of immune/cytokine signaling associate with pathologic complete response (pCR).
View Article and Find Full Text PDFCancer Cell
November 2024
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:
Harrold et al. evaluate the fertility impact of checkpoint inhibitor blockade (ICB), demonstrating that unlike in utero exposure, post-exposure conception appears to result in uncomplicated pregnancies and healthy progeny. They demonstrate contemporaneous monitoring of temporal female hormonal fluctuations before, on, and post ICB exposure and prior to successful embryo implantation.
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