Immune suppressive microenvironment in liver metastases contributes to organ-specific response of immunotherapy in advanced non-small cell lung cancer.

Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Print Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE

Publication: 2020- : London, United Kingdom : BMJ Publishing Group Ltd.
Original Publication: London : BioMed Central, 2013-

Carcinoma, Non-Small-Cell Lung*/drug therapy ; Lung Neoplasms*/drug therapy ; Liver Neoplasms*/therapy; Humans ; CD8-Positive T-Lymphocytes ; Cohort Studies ; Immunotherapy ; Tumor Microenvironment

Background: The liver is a frequent site of metastases and liver metastases (LM) correlate with diminished immunotherapy efficacy in non-small cell lung cancer (NSCLC). This study aimed to analyze whether tumor response to immunotherapy differs between pulmonary lesions (PL) and LM in NSCLC and to explore potential mechanisms through multiomics analysis.
Methods: This observational longitudinal clinical cohort study included patients with NSCLC with LM receiving immunotherapy was conducted to evaluate organ-specific tumor response of PL and LM. We collected paired PL and LM tumor samples to analyze the organ-specific difference using whole-exome sequencing, RNA sequencing, and multiplex immunohistochemistry.
Results: A total of 52 patients with NSCLC with LM were enrolled to evaluate the organ-specific response of immunotherapy. The objective response rate (21.1% vs 32.7%) and disease control rate of LM were lower than that of PL (67.3% vs 86.5%). One-third of patients showed mixed response, among whom 88.2% (15/17) presented with LM increasing, but PL decreasing, while the others had the opposite pattern (p=0.002). In another independent cohort, 27 pairs of matched PL and LM tumor samples from the same individuals, including six simultaneously collected pairs, were included in the translational part. Genomic landscapes profiling revealed similar somatic mutations, tumor mutational burden, and neoantigen number between PL and LM. Bulk-RNA sequencing showed immune activation-related genes including CD8A , LCK , and ICOS were downregulated in LM. The antigen processing and presentation, natural killer (NK) cell-mediated cytotoxicity and T-cell receptor signaling pathway were enriched in PL compared with LM. Multiplex immunohistochemistry detected significantly lower fractions of CD8 ⁺ cells (p=0.036) and CD56 ^dim+ cells (p=0.016) in LM compared with PL. Single-cell RNA sequencing also characterized lower effector CD8 ⁺ T cells activation and NK cells cytotoxicity in LM.
Conclusions: Compared with PL, LM presents an inferior organ-specific tumor response to immunotherapy. PL and LM showed limited heterogeneity in the genomic landscape, while the LM tumor microenvironment displayed lower levels of immune activation and infiltration than PL, which might contribute to developing precise immunotherapy strategies for patients with NSCLC with LM.
Competing Interests: Competing interests: QZ reports honoraria from AstraZeneca, Boehringer Ingelheim, BMS, EliLilly, MSD, Pfizer, Roche, and Sanofi, outside the submitted work. Y-LW reports personal financial interests: consulting and advisory services, speaking engagements of Roche, AstraZeneca, EliLilly, Boehringer Ingelheim, Sanofi, MSD, and BMS. LY is an employee of Nanjing Geenseeq Technology. All remaining authors declared no competing interests.
(© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immun Inflamm Dis. 2017 Feb 23;5(1):85-94. (PMID: 28250928)
Br J Cancer. 2016 Nov 8;115(10):1186-1192. (PMID: 27701388)
Cancer Immunol Immunother. 2018 Dec;67(12):1825-1832. (PMID: 30171269)
Nat Methods. 2015 May;12(5):453-7. (PMID: 25822800)
Cell. 2017 Aug 24;170(5):927-938.e20. (PMID: 28841418)
Nat Commun. 2020 May 8;11(1):2285. (PMID: 32385277)
Nat Rev Dis Primers. 2021 Apr 15;7(1):27. (PMID: 33859205)
J Clin Invest. 2020 May 1;130(5):2560-2569. (PMID: 32027620)
Annu Rev Immunol. 2011;29:235-71. (PMID: 21219185)
Cancer Immunol Res. 2015 Sep;3(9):1017-29. (PMID: 26014097)
Sci Immunol. 2020 Oct 2;5(52):. (PMID: 33008914)
Nat Commun. 2016 Aug 30;7:12624. (PMID: 27571927)
Cancer Res. 1995 Jun 1;55(11):2470-5. (PMID: 7758001)
Oncologist. 2017 Jan;22(1):61-69. (PMID: 28126915)
Oncologist. 2021 Dec;26(12):e2143-e2150. (PMID: 34288239)
Liver Cancer. 2019 Nov;8(6):480-490. (PMID: 31799205)
Clin Cancer Res. 2019 Aug 15;25(16):5015-5026. (PMID: 31085721)
J Immunother Cancer. 2022 Sep;10(9):. (PMID: 36096531)
Genome Biol. 2021 May 13;22(1):154. (PMID: 33985562)
Nat Rev Clin Oncol. 2021 Oct;18(10):625-644. (PMID: 34168333)
Chin Med J (Engl). 2022 Jun 20;135(12):1404-1413. (PMID: 35869859)
Immunity. 2020 Jan 14;52(1):17-35. (PMID: 31940268)
Int J Mol Sci. 2020 Nov 09;21(21):. (PMID: 33182504)
Nat Med. 2021 Aug;27(8):1410-1418. (PMID: 34385708)
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517)
Oncotarget. 2015 Sep 22;6(28):24990-5002. (PMID: 26317902)
Annu Rev Immunol. 2018 Apr 26;36:247-277. (PMID: 29328785)
Curr Oncol Rep. 2021 Jul 16;23(9):100. (PMID: 34269922)
Nat Med. 2021 Jan;27(1):152-164. (PMID: 33398162)
BMC Bioinformatics. 2019 May 22;20(1):264. (PMID: 31117948)
Cell. 2021 Mar 4;184(5):1281-1298.e26. (PMID: 33592174)
Mol Ther. 2014 Jan;22(1):18-27. (PMID: 24048441)
Nat Rev Gastroenterol Hepatol. 2016 Feb;13(2):88-110. (PMID: 26758786)

Keywords: Immunotherapy; Liver Neoplasms; Lung Neoplasms; Non-Small Cell Lung Cancer; Tumor Microenvironment

Date Created: 20230718 Date Completed: 20230721 Latest Revision: 20230724

20231215

PMC10357800

10.1136/jitc-2023-007218

37463790