HOXC9 Characterizes a Suppressive Tumor Immune Microenvironment and Integration with Multiple Immune Biomarkers Predicts Response to PD-1 Blockade Plus Chemotherapy in Lung Adenocarcinoma

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2024 Mar 6

PMID 38446596

Authors

Liang Liu

Zhenshan Zhang

Chenxue Jiang

Yaoyao Zhu

Ruiqin Han

Leilei Wu

Yaping Xu

Affiliations

Soon will be listed here.

Abstract

Background: The quest for dependable biomarkers to predict responses to immune checkpoint inhibitors (ICIs) combined with chemotherapy in advanced non-small cell lung cancer remains unfulfilled. HOXC9, known for its role in oncogenesis and creating a suppressive tumor microenvironment (TME), shows promise in enhancing predictive precision when included as a TME biomarker. This study explores the predictive significance of HOXC9 for ICI plus chemotherapy efficacy in lung adenocarcinoma (LUAD).

Methods: Following the bioinformatic findings, assays were performed to ascertain the effects of Hoxc9 on oncogenesis and response to programmed death 1 (PD-1) blockade. Furthermore, a cohort of LUAD patients were prospectively enrolled to receive anti-PD-1 plus chemotherapy. Based on the expression levels, baseline characteristics, and clinical outcomes, the predictive potential of HOXC9, PD-L1, CD4, CD8, CD68, and FOXP3 was integrally analyzed. HOXC9 not only mediated oncogenesis, but also corelated with suppressive TME. CMT167 and LLC cell lines unveiled the impacts of Hoxc9 on proliferation, invasion, and migration. Subsequently, tumor-bearing murine models were established to validate the inverse relationship between Hoxc9 expression and effective CD8+ T cells.

Results: Inhibition of Hoxc9 significantly curtailed tumor growth (P<0.05), independent of PD-1 blockade. In patient studies, while individual markers fell short in prognosticating survival, a notable elevation in CD8-positive expression was observed in responders (P=0.042). Yet, the amalgamation of HOXC9 with other markers provided a more distinct differentiation between responders and non-responders. Notably, patients displaying PD-L1+/HOXC9- and CD8+/HOXC9- phenotypes exhibited significantly prolonged progression-free survival.

Conclusions: The expression of HOXC9 may serve as a biomarker to amplifying predictive efficacy for ICIs plus chemotherapy, which is also a viable oncogene and therapeutic target for immunotherapy in LUAD.

Citing Articles

Integrated Analysis Reveals COL4A3 as a Novel Diagnostic and Therapeutic Target in UV-Related Skin Cutaneous Melanoma.

Yao Z, Lu L, Xu Q, Hua S, Wang H, Jiang H Clin Cosmet Investig Dermatol. 2024; 17:1429-1446.

PMID: 38911338 PMC: 11192641. DOI: 10.2147/CCID.S461959.

References

Shirasawa M, Yoshida T, Shimoda Y, Takayanagi D, Shiraishi K, Kubo T . Differential Immune-Related Microenvironment Determines Programmed Cell Death Protein-1/Programmed Death-Ligand 1 Blockade Efficacy in Patients With Advanced NSCLC. J Thorac Oncol. 2021; 16(12):2078-2090. DOI: 10.1016/j.jtho.2021.07.027. View

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J . Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med. 2020; 9(3):305-314. DOI: 10.1016/S2213-2600(20)30365-9. View

Zhang L, Chen Y, Wang H, Xu Z, Wang Y, Li S . Massive PD-L1 and CD8 double positive TILs characterize an immunosuppressive microenvironment with high mutational burden in lung cancer. J Immunother Cancer. 2021; 9(6). PMC: 8212410. DOI: 10.1136/jitc-2021-002356. View

Zhou C, Wang Z, Sun Y, Cao L, Ma Z, Wu R . Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trial. Lancet Oncol. 2022; 23(2):220-233. DOI: 10.1016/S1470-2045(21)00650-1. View

Hur H, Lee J, Yang S, Kim J, Park A, Kim M . HOXC9 Induces Phenotypic Switching between Proliferation and Invasion in Breast Cancer Cells. J Cancer. 2016; 7(7):768-73. PMC: 4860792. DOI: 10.7150/jca.13894. View

Cerami E, Gao J, Dogrusoz U, Gross B, Sumer S, Aksoy B . The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012; 2(5):401-4. PMC: 3956037. DOI: 10.1158/2159-8290.CD-12-0095. View

Liu J, Lichtenberg T, Hoadley K, Poisson L, Lazar A, Cherniack A . An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics. Cell. 2018; 173(2):400-416.e11. PMC: 6066282. DOI: 10.1016/j.cell.2018.02.052. View

Hu M, Ou-Yang W, Jing D, Chen R . Clinical Prognostic Significance of HOXC9 Expression in Patients with Colorectal Cancer. Clin Lab. 2019; 65(8). DOI: 10.7754/Clin.Lab.2019.190122. View

10.

Grell P, Borilova S, Fabian P, Selingerova I, Novak D, Muller P . FoxP3 Expression in Tumor-Infiltrating Lymphocytes as Potential Predictor of Response to Immune Checkpoint Inhibitors in Patients with Advanced Melanoma and Non-Small Cell Lung Cancer. Cancers (Basel). 2023; 15(6). PMC: 10047850. DOI: 10.3390/cancers15061901. View

11.

Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F . Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 378(22):2078-2092. DOI: 10.1056/NEJMoa1801005. View

12.

Carnesecchi J, Pinto P, Lohmann I . Hox transcription factors: an overview of multi-step regulators of gene expression. Int J Dev Biol. 2019; 62(11-12):723-732. DOI: 10.1387/ijdb.180294il. View

13.

Gao J, Aksoy B, Dogrusoz U, Dresdner G, Gross B, Sumer S . Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013; 6(269):pl1. PMC: 4160307. DOI: 10.1126/scisignal.2004088. View

14.

Cassetta L, Pollard J . A timeline of tumour-associated macrophage biology. Nat Rev Cancer. 2023; 23(4):238-257. DOI: 10.1038/s41568-022-00547-1. View

15.

Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2008; 45(2):228-47. DOI: 10.1016/j.ejca.2008.10.026. View

16.

Cheng B, Ding K, Chen P, Ji J, Luo T, Guo X . Anti-PD-L1/TGF-βR fusion protein (SHR-1701) overcomes disrupted lymphocyte recovery-induced resistance to PD-1/PD-L1 inhibitors in lung cancer. Cancer Commun (Lond). 2022; 42(1):17-36. PMC: 8753312. DOI: 10.1002/cac2.12244. View

17.

Bi R, Wei W, Lu Y, Hu F, Yang X, Zhong Y . High hsa_circ_0020123 expression indicates poor progression to non-small cell lung cancer by regulating the miR-495/HOXC9 axis. Aging (Albany NY). 2020; 12(17):17343-17352. PMC: 7521531. DOI: 10.18632/aging.103722. View

18.

Bai M, Wu L, Zhao M, Jin P, Liu J, Wang W . Integrated analysis of EGFR mutated non-small cell lung cancer reveals two distinct molecular subtypes. Clin Transl Med. 2023; 13(10):e1431. PMC: 10570769. DOI: 10.1002/ctm2.1431. View

19.

Grant M, Herbst R, Goldberg S . Selecting the optimal immunotherapy regimen in driver-negative metastatic NSCLC. Nat Rev Clin Oncol. 2021; 18(10):625-644. DOI: 10.1038/s41571-021-00520-1. View

20.

Teng M, Ngiow S, Ribas A, Smyth M . Classifying Cancers Based on T-cell Infiltration and PD-L1. Cancer Res. 2015; 75(11):2139-45. PMC: 4452411. DOI: 10.1158/0008-5472.CAN-15-0255. View