Uncovering the Role of Tumor CGAS Expression in Predicting Response to PD-1/L1 Inhibitors in Non-small Cell Lung Cancer

Overview

Journal Cancer Immunol Immunother

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2024 Nov 2

PMID 39487921

Authors

Yuichi Ozawa

Yasuhiro Koh

Ryota Shibaki

Yuhei Harutani

Hiroaki Akamatsu

Atsushi Hayata

Takeya Sugimoto

Yuka Kitamura

Junya Fukuoka

Masanori Nakanishi

Nobuyuki Yamamoto

Affiliations

Soon will be listed here.

Abstract

Objectives: The impact of cGAS/STING tumor expression on PD-1/L1 inhibitor efficacy and the tumor microenvironment remain to be elucidated.

Methods: In a post-hoc analysis of a prospective biomarker study with 106 advanced NSCLC patients treated with PD-1/L1 inhibitors from December 2015 to September 2018, tumor tissue before treatment from 68 patients was analyzed. cGAS and STING expression were measured using immunohistochemical staining and H-scores. Additionally, 40 serum proteins were quantified before and 4-6 weeks after treatment initiation.

Results: Median cGAS and STING H-scores were 220 (range, 5-300) and 190 (range, 0-300), respectively. There were no differences in cGAS or STING H-scores between the high (tumor proportion score [TPS] ≥ 50) and low (TPS < 50) PD-L1groups (p = 0.990 and 0.283, respectively). Unexpectedly, patients with high cGAS (H-score ≥ 220) demonstrated significantly shorter progression-free survival (PFS) of PD-1/L1 inhibitors when the PD-L1 TPS was high (median PFS: 143 days vs. not reached; p = 0.028); PFS at 18 months was 7% and 53% in the high and low cGAS groups, respectively while STING expression did not impact PFS. In serum protein analyses, high cGAS H-score was associated with significantly higher TGF-β1 and TGF-β2 before PD-1/L1 inhibition (47.5 vs. 22.3 ng/l, p = 0.023; 2118 vs. 882 pg/ml, p = 0.037); additionally, the cGAS H-score significantly correlated with TGF-β1 (r = 0.451, p = 0.009) and TGF-β2 (r = 0.375, p = 0.031) basal levels.

Conclusion: cGAS expression, but not STING, predicts poor PD-1/L1 inhibitor efficacy in NSCLC with high PD-L1, potentially due to a TGF-β-mediated immunosuppressive environment (UMIN000024414).

References

Akamatsu H, Murakami E, Oyanagi J, Shibaki R, Kaki T, Takase E . Immune-Related Adverse Events by Immune Checkpoint Inhibitors Significantly Predict Durable Efficacy Even in Responders with Advanced Non-Small Cell Lung Cancer. Oncologist. 2020; 25(4):e679-e683. PMC: 7160399. DOI: 10.1634/theoncologist.2019-0299. View

Cheon H, Holvey-Bates E, McGrail D, Stark G . PD-L1 sustains chronic, cancer cell-intrinsic responses to type I interferon, enhancing resistance to DNA damage. Proc Natl Acad Sci U S A. 2021; 118(47). PMC: 8617513. DOI: 10.1073/pnas.2112258118. View

Gordon S, Maute R, Dulken B, Hutter G, George B, McCracken M . PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017; 545(7655):495-499. PMC: 5931375. DOI: 10.1038/nature22396. View

Kim Y, Cho N, Jin L, Jin H, Kang G . Prognostic significance of STING expression in solid tumor: a systematic review and meta-analysis. Front Oncol. 2023; 13:1244962. PMC: 10497868. DOI: 10.3389/fonc.2023.1244962. View

Decout A, Katz J, Venkatraman S, Ablasser A . The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021; 21(9):548-569. PMC: 8029610. DOI: 10.1038/s41577-021-00524-z. View

Du S, Chen G, Yang P, Chen Y, Hu Y, Zhao Q . Radiation Therapy Promotes Hepatocellular Carcinoma Immune Cloaking via PD-L1 Upregulation Induced by cGAS-STING Activation. Int J Radiat Oncol Biol Phys. 2022; 112(5):1243-1255. DOI: 10.1016/j.ijrobp.2021.12.162. View

Barber G . STING: infection, inflammation and cancer. Nat Rev Immunol. 2015; 15(12):760-70. PMC: 5004891. DOI: 10.1038/nri3921. View

Cheng H, Xu Q, Lu X, Yuan H, Li T, Zhang Y . Activation of STING by cGAMP Regulates MDSCs to Suppress Tumor Metastasis Reversing Epithelial-Mesenchymal Transition. Front Oncol. 2020; 10:896. PMC: 7300176. DOI: 10.3389/fonc.2020.00896. View

Motwani M, Pesiridis S, Fitzgerald K . DNA sensing by the cGAS-STING pathway in health and disease. Nat Rev Genet. 2019; 20(11):657-674. DOI: 10.1038/s41576-019-0151-1. View

10.

Zhu Y, An X, Zhang X, Qiao Y, Zheng T, Li X . STING: a master regulator in the cancer-immunity cycle. Mol Cancer. 2019; 18(1):152. PMC: 6827255. DOI: 10.1186/s12943-019-1087-y. View

11.

Downey C, Aghaei M, Schwendener R, Jirik F . DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2'3'-cGAMP, induces M2 macrophage repolarization. PLoS One. 2014; 9(6):e99988. PMC: 4062468. DOI: 10.1371/journal.pone.0099988. View

12.

Yang L, Pang Y, Moses H . TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010; 31(6):220-7. PMC: 2891151. DOI: 10.1016/j.it.2010.04.002. View

13.

Sasaki N, Homme M, Kitajima S . Targeting the loss of cGAS/STING signaling in cancer. Cancer Sci. 2023; 114(10):3806-3815. PMC: 10551601. DOI: 10.1111/cas.15913. View

14.

Ahn J, Xia T, Capote A, Betancourt D, Barber G . Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells. Cancer Cell. 2018; 33(5):862-873.e5. PMC: 6177226. DOI: 10.1016/j.ccell.2018.03.027. View

15.

Mok T, Wu Y, Kudaba I, Kowalski D, Cho B, Turna H . Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019; 393(10183):1819-1830. DOI: 10.1016/S0140-6736(18)32409-7. View

16.

Cho W, Won S, Choi Y, Yi S, Park J, Park J . Targeted Protein Upregulation of STING for Boosting the Efficacy of Immunotherapy. Angew Chem Int Ed Engl. 2023; 62(18):e202300978. DOI: 10.1002/anie.202300978. View

17.

Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B . Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 2019; 18(1):10. PMC: 6332843. DOI: 10.1186/s12943-018-0928-4. View

18.

Herbst R, Baas P, Kim D, Felip E, Perez-Gracia J, Han J . Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2015; 387(10027):1540-1550. DOI: 10.1016/S0140-6736(15)01281-7. View

19.

Wang X, Lin M, Zhu L, Ye Z . GAS-STING: a classical DNA recognition pathways to tumor therapy. Front Immunol. 2023; 14:1200245. PMC: 10618366. DOI: 10.3389/fimmu.2023.1200245. View

20.

Ozawa Y, Harutani Y, Oyanagi J, Akamatsu H, Murakami E, Shibaki R . CD24, not CD47, negatively impacts upon response to PD-1/L1 inhibitors in non-small-cell lung cancer with PD-L1 tumor proportion score < 50. Cancer Sci. 2020; 112(1):72-80. PMC: 7780034. DOI: 10.1111/cas.14705. View