Tumor Microenvironment Landscape of NSCLC Reveals Resistance Mechanisms for Programmed Death-Ligand 1 Blockade After Chemoradiotherapy: A Multicenter Prospective Biomarker Study (WJOG11518L:SUBMARINE)

Koji Haratani; Atsushi Nakamura; Nobuaki Mamesaya; Shigeki Mitsuoka; Yasuto Yoneshima; Ryota Saito; Junko Tanizaki; Yasuhito Fujisaka; Akito Hata; Kosuke Tsuruno; Tomohiro Sakamoto; Shunsuke Teraoka; Masahide Oki; Hiroshi Watanabe; Yuki Sato; Yusuke Nakano; Tomoyuki Otani; Kazuko Sakai; Shuta Tomida; Yasutaka Chiba; Akihiko Ito; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Hidetoshi Hayashi

doi:10.1016/j.jtho.2023.06.012

Tumor Microenvironment Landscape of NSCLC Reveals Resistance Mechanisms for Programmed Death-Ligand 1 Blockade After Chemoradiotherapy: A Multicenter Prospective Biomarker Study (WJOG11518L:SUBMARINE)

J Thorac Oncol. 2023 Oct;18(10):1334-1350. doi: 10.1016/j.jtho.2023.06.012. Epub 2023 Jun 25.

Authors

Koji Haratani¹, Atsushi Nakamura², Nobuaki Mamesaya³, Shigeki Mitsuoka⁴, Yasuto Yoneshima⁵, Ryota Saito⁶, Junko Tanizaki⁷, Yasuhito Fujisaka⁸, Akito Hata⁹, Kosuke Tsuruno¹⁰, Tomohiro Sakamoto¹¹, Shunsuke Teraoka¹², Masahide Oki¹³, Hiroshi Watanabe¹⁴, Yuki Sato¹⁵, Yusuke Nakano¹⁶, Tomoyuki Otani¹⁷, Kazuko Sakai¹⁸, Shuta Tomida¹⁹, Yasutaka Chiba²⁰, Akihiko Ito¹⁷, Kazuto Nishio¹⁸, Nobuyuki Yamamoto¹², Kazuhiko Nakagawa²¹, Hidetoshi Hayashi²¹

Affiliations

¹ Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan. Electronic address: haratani_k@med.kindai.ac.jp.
² Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Miyagi, Japan.
³ Division of Thoracic Oncology, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan.
⁴ Department of Clinical Oncology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Osaka, Japan.
⁵ Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan.
⁶ Department of Respiratory Medicine, Tohoku University School of Medicine, Sendai, Miyagi, Japan.
⁷ Division of Medical Oncology, Kishiwada City Hospital, Kishiwada, Osaka, Japan.
⁸ Medical Oncology, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan.
⁹ Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center, Kobe, Hyogo, Japan.
¹⁰ Department of Respiratory Medicine, Iizuka Hospital, Iizuka, Fukuoka, Japan.
¹¹ Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan.
¹² Internal Medicine III, Wakayama Medical University, Wakayama, Wakayama, Japan.
¹³ Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, Japan.
¹⁴ Department of Respiratory Medicine, Saka General Hospital, Shiogama, Miyagi, Japan.
¹⁵ Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan.
¹⁶ Department of Medical Oncology, Izumi City General Hospital, Izumi, Osaka, Japan.
¹⁷ Department of Pathology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
¹⁸ Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
¹⁹ Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Okayama, Japan.
²⁰ Clinical Research Center, Kindai University Hospital, Osaka-Sayama, Osaka, Japan.
²¹ Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.

PMID: 37364849
DOI: 10.1016/j.jtho.2023.06.012

Abstract

Introduction: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III NSCLC. Nevertheless, approximately half of the treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L:SUBMARINE).

Methods: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue and flow cytometric analysis of circulating immune cells. Progression-free survival was compared on the basis of these biomarkers.

Results: The importance of preexisting effective adaptive immunity in tumors was revealed for treatment benefit regardless of genomic features. We also identified CD73 expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8⁺ tumor-infiltrating lymphocyte density and the high CD73⁺ cancer cells were independently associated with poor durvalumab outcome (hazard ratios = 4.05 [95% confidence interval: 1.17-14.04] for CD8⁺ tumor-infiltrating lymphocytes; 4.79 [95% confidence interval: 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity.

Conclusions: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.

Keywords: Durvalumab; PACIFIC regimen; Resistance mechanism; Tumor microenvironment; Unresectable stage III non–small cell lung cancer.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / analysis
Biomarkers, Tumor / genetics
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Chemoradiotherapy
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Neoplasm Staging
Tumor Microenvironment

Substances

Biomarkers, Tumor
CD274 protein, human