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Limited Immune-Mediated Efficacy of Anti-PD-L1/VEGF in EGFR-TKI-Naïve Egfr-Mutant Lung Cancer with Non-Inflamed Tumor Microenvironment
by
, , , , , , ,
Atsuko Hirabae
1, 
Tadahiro Kuribayashi
1,
Shuta Tomida
2,
Sachi Okawa
1,
Takamasa Nakasuka
1,
Kazuya Nishii
1,
Jun Nishimura
1,
Go Makimoto
3,
Kiichiro Ninomiya
2,
Hisao Higo
1,
Kammei Rai
4,
Eiki Ichihara
5,
Katsuyuki Hotta
4,
Masamichi Sugimoto
6,
Yosuke Togashi
3,
Yoshinobu Maeda
1,
Katsuyuki Kiura
3 and
Kadoaki Ohashi
3,* 1
Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan
2
Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama 700-8558, Japan
3
Department of Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan
4
Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700-8558, Japan
5
Center for Clinical Oncology, Okayama University Hospital, Okayama 700-8558, Japan
6
Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura 247-8530, Japan
*
Author to whom correspondence should be addressed.
Curr. Oncol. 2026, 33(6), 315; https://doi.org/10.3390/curroncol33060315
Submission received: 8 April 2026
/
Revised: 15 May 2026
/
Accepted: 25 May 2026
/
Published: 27 May 2026
(This article belongs to the Section Thoracic Oncology)
Simple Summary
Lung cancers with mutations in the epidermal growth factor receptor gene often respond poorly to immune checkpoint inhibitors, largely because the tumor environment lacks sufficient immune activity. Some clinical trials have tested whether adding a drug targeting tumor blood vessels to immunotherapy and chemotherapy could overcome this limitation, but results have been inconsistent. A key question is whether such drugs can activate the immune system in tumors not yet exposed to targeted therapies. We investigated this in a mouse model mimicking the poorly immunogenic environment of human EGFR-mutant lung cancer before targeted therapy and found that the anti-VEGF drug we tested did not activate the immune system or improve checkpoint inhibitor effectiveness. However, combining paclitaxel with this drug suppressed tumor growth through a mechanism that did not rely on T cells, with increased natural killer cell infiltration. These findings suggest that future immunotherapy strategies may need to engage immune pathways beyond T-cell responses.
Abstract
Immune checkpoint inhibitors (ICIs) show limited efficacy in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma due to its non-inflamed tumor microenvironment (TME). While quadruple therapy combining chemotherapy, anti-programmed death-ligand 1 (PD-L1), and anti-vascular endothelial growth factor (VEGF) antibodies has shown inconsistent results in EGFR-tyrosine kinase inhibitor (TKI)-pretreated patients, whether anti-VEGF therapy can modulate the intrinsic non-inflamed TME remains unknown. We employed an EGFR-TKI-naïve syngeneic Egfr-mutant mouse model and evaluated effects of anti-VEGF, anti-PD-L1, carboplatin, and paclitaxel as monotherapies and combinations, with TME analysis via immunohistochemistry (IHC), flow cytometry, and RNA sequencing. Anti-PD-L1 showed no antitumor effect, and adding anti-VEGF failed to convert the TME to an inflamed status. Although paclitaxel—but not carboplatin—combined with low-dose anti-VEGF inhibited tumor growth, adding anti-PD-L1 provided no benefit, indicating the anti-VEGF-A antibody evaluated here has a limited role in sensitizing tumors to anti-PD-L1 regardless of chemotherapy. CD8+ T-cell depletion did not attenuate the effect of paclitaxel plus low-dose anti-VEGF, and IHC and RNA sequencing revealed increased natural killer cell infiltration, suggesting a CD8+ T-cell-independent, innate immune mechanism. These findings provide preclinical evidence that the evaluated anti-VEGF has limited immunomodulatory activity in EGFR-TKI-naïve Egfr-mutant tumors with a non-inflamed TME, and suggest immunotherapeutic strategies beyond CD8+ T-cell-mediated immunity warrant investigation.
