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Article Open Access

Lectin‑captured plasma microRNAs predict response and survival in patients with non‑small cell lung cancer treated with nivolumab

  • Authors:
    • Eiji Narusawa
    • Yukiko Nakano
    • Seshiru Nakazawa
    • Kanji Hori
    • Yoichi Ohtaki
    • Natsuko Kawatani
    • Tomohiro Yazawa
    • Ryohei Yoshikawa
    • Kazuki Numajiri
    • Ryo Kuriyama
    • Hiroshi Kurokawa
    • Yoshihiro Taguchi
    • Seyed Mostafa Mostafavi Zadeh
    • Haruka Okami
    • Takuya Shiraishi
    • Nobuhiro Nakazawa
    • Takamichi Igarashi
    • Kyoichi Kaira
    • Hiroshi Saeki
    • Ken Shirabe
    • Takehiko Yokobori
  • View Affiliations / Copyright

    Affiliations: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371‑8511, Japan, The IT Lab Co., Ltd., Morioka, Iwate 020‑0857, Japan, Division of Gene Therapy Science, Gunma University, Initiative for Advanced Research, Maebashi, Gunma 371‑8511, Japan, Department of Respiration Medicine, Saitama Medical University, International Medical Center, Hidaka, Saitama 350‑1298, Japan
    Copyright: © Narusawa et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 314
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    Published online on: May 25, 2026
       https://doi.org/10.3892/ol.2026.15669
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Abstract

Predictive biomarkers for response and post‑treatment survival of patients with non‑small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) are limited. The present study aimed to evaluate whether recombinant Oscillatoria agardhii agglutinin (OAA)1‑enriched plasma microRNAs (miRNAs/miRs) can serve as predictive and prognostic biomarkers in patients with NSCLC treated with nivolumab. High‑mannose glycans, enriched in tumors, were selectively captured using this novel lectin. Pre‑treatment plasma samples from 48 patients with NSCLC treated with nivolumab, an ICI, were processed using OAA1 columns. Plasma miRNAs were evaluated for their potential roles as predictive markers of response to nivolumab. The levels of circulating miR‑320a, miR‑320b and miR‑3613‑5p, which are associated with nivolumab resistance, were quantified with and without OAA1 enrichment. The three miRNAs were significantly upregulated in patients with stable or progressive disease compared with those with a partial response. For miR‑320a, this difference was significant only after OAA1 enrichment. Receiver operating characteristic curve and survival analyses showed improved predictive and prognostic performance for OAA1‑enriched miRNAs: The area under the curve for miR‑3613‑5p improved from 0.837 to 0.897, and the hazard ratio increased from 3.386 to 7.815. In conclusion, OAA1‑enriched plasma miRNAs may be associated with resistance to nivolumab and a poor prognosis in NSCLC. This glycan‑based enrichment strategy could enhance the clinical value of circulating miRNAs and may complement tissue‑based biomarkers of ICI response.
View Figures

Figure 1

Identification of circulating
OAA1-captured miRNAs associated with lung cancer and resistance to
nivolumab. (A) Lectin histochemistry using OAA1 on surgically
resected lung cancer tissues (×200 magnification). The left panel
shows OAA1 lectin staining in normal lung tissue, whereas the right
panel shows OAA1 lectin staining in lung cancer tissue. (B) In the
discovery phase, plasma samples from two patients with NSCLC with
PD were collected before and after nivolumab treatment. After
plasma purification using an OAA1 column, microarray analysis was
performed to identify candidate miRNAs (miR-320a, miR-320b, and
miR-3613-5p) associated with nivolumab resistance. In the
validation phase, plasma samples from 48 patients with NSCLC
(before nivolumab treatment) were analyzed with and without OAA1
column purification. The levels of the identified miRNAs were
quantified using TaqMan qPCR, and statistical analyses were
conducted to evaluate their predictive and prognostic values as
biomarkers for nivolumab resistance. (C) Microarray analysis of
OAA1-captured plasma miRNAs in patients with PD after nivolumab
treatment reveals several upregulated candidate miRNAs, including
miR-320a, miR-320b, and miR-3613-5p. (D) Relative levels of
miR-320a, miR-320b, and miR-3613-5p in pre-treatment plasma from
patients with NSCLC (n=48) and healthy controls (n=11) with and
without OAA1 enrichment. Plasma miRNA levels were quantified by
reverse transcription-qPCR. Relative miRNA levels were normalized
to miR-16-5p and calculated using the 2−ΔΔCq method,
with the mean level of healthy volunteers serving as the
calibrator. Statistical significance was determined using the
Mann-Whitney U test. Data are presented as median with 95%
confidence intervals. miRNA/miR, microRNA; NSCLC, non-small cell
lung cancer; OAA1, Oscillatoria agardhii agglutinin 1; PD,
progressive disease; qPCR, quantitative polymerase chain
reaction.

Figure 2

Differential expression of miR-320a,
miR-320b, and miR-3613-5p in pre-treatment plasma from patients
with non-small cell lung cancer with PR or SD + PD. (A) Relative
levels of miR-320a, miR-320b, and miR-3613-5p without OAA1
enrichment. (B) With OAA1 column enrichment. Plasma miRNA levels
were quantified by reverse transcription-quantitative polymerase
chain reaction and are shown as relative abundance using the
2−ΔCq method normalized to miR-16-5p. Statistical
significance was determined using the Mann-Whitney U test. Data are
presented as median with 95% confidence intervals. miR, microRNA;
OAA1, Oscillatoria agardhii agglutinin 1; SD, stable
disease; PD, progressive disease; PR, partial response.

Figure 3

ROC curve analysis of miRNAs for
predicting non-response to immune checkpoint inhibitor therapy in
patients with non-small cell lung cancer treated with nivolumab.
(A) ROC curves for circulating miR-320a, miR-320b, and miR-3613-5p
without OAA1 column enrichment. (B) With OAA1 enrichment. AUC, area
under the curve; CI, confidence interval; miR, microRNA; OAA1,
Oscillatoria agardhii agglutinin 1; ROC, receiver operating
characteristic.

Figure 4

Kaplan-Meier analysis for OS based on
pre-treatment plasma levels of miR-320a, miR-320b, and miR-3613-5p
in patients with non-small cell lung cancer treated with nivolumab
(n=48). (A) Kaplan-Meier curves comparing the OS between the high-
and low-expression groups for each miRNA without OAA1 column
enrichment. (B) Kaplan-Meier curves for the same miRNAs with the
OAA1 enrichment. The number of patients in each group is indicated
in the legends. Cutoff values for high/low expression were
determined using receiver operating characteristic analysis.
P-values are shown; *P<0.05. miR, microRNA; OAA1,
Oscillatoria agardhii agglutinin 1; OS, overall
survival.
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Copy and paste a formatted citation
Spandidos Publications style
Narusawa E, Nakano Y, Nakazawa S, Hori K, Ohtaki Y, Kawatani N, Yazawa T, Yoshikawa R, Numajiri K, Kuriyama R, Kuriyama R, et al: Lectin‑captured plasma microRNAs predict response and survival in patients with non‑small cell lung cancer treated with nivolumab. Oncol Lett 32: 314, 2026.
APA
Narusawa, E., Nakano, Y., Nakazawa, S., Hori, K., Ohtaki, Y., Kawatani, N. ... Yokobori, T. (2026). Lectin‑captured plasma microRNAs predict response and survival in patients with non‑small cell lung cancer treated with nivolumab. Oncology Letters, 32, 314. https://doi.org/10.3892/ol.2026.15669
MLA
Narusawa, E., Nakano, Y., Nakazawa, S., Hori, K., Ohtaki, Y., Kawatani, N., Yazawa, T., Yoshikawa, R., Numajiri, K., Kuriyama, R., Kurokawa, H., Taguchi, Y., Mostafavi Zadeh, S., Okami, H., Shiraishi, T., Nakazawa, N., Igarashi, T., Kaira, K., Saeki, H., Shirabe, K., Yokobori, T."Lectin‑captured plasma microRNAs predict response and survival in patients with non‑small cell lung cancer treated with nivolumab". Oncology Letters 32.1 (2026): 314.
Chicago
Narusawa, E., Nakano, Y., Nakazawa, S., Hori, K., Ohtaki, Y., Kawatani, N., Yazawa, T., Yoshikawa, R., Numajiri, K., Kuriyama, R., Kurokawa, H., Taguchi, Y., Mostafavi Zadeh, S., Okami, H., Shiraishi, T., Nakazawa, N., Igarashi, T., Kaira, K., Saeki, H., Shirabe, K., Yokobori, T."Lectin‑captured plasma microRNAs predict response and survival in patients with non‑small cell lung cancer treated with nivolumab". Oncology Letters 32, no. 1 (2026): 314. https://doi.org/10.3892/ol.2026.15669
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x
Spandidos Publications style
Narusawa E, Nakano Y, Nakazawa S, Hori K, Ohtaki Y, Kawatani N, Yazawa T, Yoshikawa R, Numajiri K, Kuriyama R, Kuriyama R, et al: Lectin‑captured plasma microRNAs predict response and survival in patients with non‑small cell lung cancer treated with nivolumab. Oncol Lett 32: 314, 2026.
APA
Narusawa, E., Nakano, Y., Nakazawa, S., Hori, K., Ohtaki, Y., Kawatani, N. ... Yokobori, T. (2026). Lectin‑captured plasma microRNAs predict response and survival in patients with non‑small cell lung cancer treated with nivolumab. Oncology Letters, 32, 314. https://doi.org/10.3892/ol.2026.15669
MLA
Narusawa, E., Nakano, Y., Nakazawa, S., Hori, K., Ohtaki, Y., Kawatani, N., Yazawa, T., Yoshikawa, R., Numajiri, K., Kuriyama, R., Kurokawa, H., Taguchi, Y., Mostafavi Zadeh, S., Okami, H., Shiraishi, T., Nakazawa, N., Igarashi, T., Kaira, K., Saeki, H., Shirabe, K., Yokobori, T."Lectin‑captured plasma microRNAs predict response and survival in patients with non‑small cell lung cancer treated with nivolumab". Oncology Letters 32.1 (2026): 314.
Chicago
Narusawa, E., Nakano, Y., Nakazawa, S., Hori, K., Ohtaki, Y., Kawatani, N., Yazawa, T., Yoshikawa, R., Numajiri, K., Kuriyama, R., Kurokawa, H., Taguchi, Y., Mostafavi Zadeh, S., Okami, H., Shiraishi, T., Nakazawa, N., Igarashi, T., Kaira, K., Saeki, H., Shirabe, K., Yokobori, T."Lectin‑captured plasma microRNAs predict response and survival in patients with non‑small cell lung cancer treated with nivolumab". Oncology Letters 32, no. 1 (2026): 314. https://doi.org/10.3892/ol.2026.15669
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