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OncoImmunology Volume 10, 2021 - Issue 1
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Original Research

YTHDF1 and YTHDF2 are associated with better patient survival and an inflamed tumor-immune microenvironment in non–small-cell lung cancer

Kazuo Tsuchiyaa Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan;b Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, JapanView further author information
,
Katsuhiro Yoshimuraa Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan;b Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, JapanView further author information
,
Yusuke Inouea Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan;b Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, JapanView further author information
,
Yuji Iwashitaa Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, JapanView further author information
,
Hidetaka Yamadaa Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, JapanView further author information
,
Akikazu Kawasec First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, JapanView further author information
,
Takuya Watanabed Division of Thoracic Surgery, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, JapanView further author information
,
Masayuki Tanahashid Division of Thoracic Surgery, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, JapanView further author information
,
Hiroshi Ogawae Department of Pathology, Seirei Mikatahara General Hospital, Hamamatsu, JapanView further author information
,
Kazuhito Funaic First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, JapanView further author information
,
Kazuya Shinmuraa Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, JapanView further author information
,
Takafumi Sudab Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, JapanView further author information
&
Haruhiko Sugimuraa Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, JapanCorrespondence[email protected]
View further author information
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Article: 1962656 | Received 16 Apr 2021, Accepted 26 Jul 2021, Published online: 10 Aug 2021

Figures & data

Figure 1. Representative images of YTHDF1, YTHDF2, and TIL expression in immunohistochemistry

(a) Representative images of immunohistochemistry of YTHDF1 and YTHDF2 (×20 magnification, inset ×60 magnification). The yellow square indicates the position of the inset. Staining intensity was categorized as 0 (absent), 1 (weak), 2 (moderate), or 3 (strong). (b) Representative images of tumor-infiltrating lymphocytes such as FOXP3+, PD-1+, CD8+, and CD45RO+ immune cells (×20 magnification).
Figure 1. Representative images of YTHDF1, YTHDF2, and TIL expression in immunohistochemistry

Figure 2. Level of YTHDF1 and YTHDF2 expression is elevated in NSCLC

(a) Comparison of the expressions of YTHDF 1, YTHDF2, and YTHDF3 in tumor and nontumor lung tissue in patients with non–small-cell lung cancer (N: nontumor tissue, T: tumor tissue). ***P < .001 and ****P < .0001, Mann–Whitney U test). Results were presented as means ± SD. (b) The histograms show the distribution of the H-scores for YTHDF1 and YTHDF2 evaluated by immunohistochemistry.
Figure 2. Level of YTHDF1 and YTHDF2 expression is elevated in NSCLC

Table 1. Comparison of clinical characteristics based on YTHDF1 and YTHDF2 expression in the tumor

Table 2. Univariate and multivariate Cox hazards model analyses for overall survival of patients with non–small-cell lung cancer

Table 3. Univariate and multivariate Cox hazards model analyses for recurrence-free survival of patients with non–small-cell lung cancer

Figure 3. Survival curves according to YTHDF1 and YTHDF2 expression in patients with non–small-cell lung cancer (NSCLC)

Kaplan–Meier survival curves for overall survival (OS) according to the expression of YTHDF1 (a) and YTHDF2 (b) (n = 603, log-rank test). Kaplan–Meier survival curves for recurrence-free survival (RFS) according to YTHDF1 (c) and YTHDF2 (d) expression (n = 603, log-rank test). Kaplan–Meier survival curves for OS according to YTHDF1 (e) and YTHDF2 (f) expression in the population who received adjuvant chemotherapy (n = 254, log-rank test).
Figure 3. Survival curves according to YTHDF1 and YTHDF2 expression in patients with non–small-cell lung cancer (NSCLC)

Figure 4. Expression of YTHDF1 and YTHDF2 is associated with tumor-infiltrating lymphocytes (TILs) in the stroma in patients with non–small-cell lung cancer

(a) Number of TILs in tumor nests according to the expression of YTHDF1 (Mann–Whitney U test). (b) Number of TILs in tumor nests according to the expression of YTHDF2 (*P < .05 and ****P < .0001, Mann–Whitney U test). (c) Number of TILs in stroma according to the expression of YTHDF1 (**P < .01 and ****P < .0001, Mann–Whitney U test). (d) Number of TILs in stroma according to the expression of YTHDF2 (***P < .001 and ****P < .0001, Mann–Whitney U test). All results were presented as means ± SEM.
Figure 4. Expression of YTHDF1 and YTHDF2 is associated with tumor-infiltrating lymphocytes (TILs) in the stroma in patients with non–small-cell lung cancer

Figure 5. YTHDF1 and YTHDF2 knockdown suppresses cell proliferation and partially induces apoptosis in lung cancer cells

YTHDF1 and YTHDF2 mRNA expression were reduced by silencing YTHDF1 (a) and YTHDF2 (b) in PC9, A549, and H1299. Results were presented as means ± SD. (c) Effect of relative cell proliferation in PC9, A549, and H1299 transfected with siRNA of YTHDF1 or YTHDF2 and control (siNC) (n = 3 for each group, *P < .05, **P < .01, ***P < .001, ****P < .0001 by two-way analysis of variance). (d) The number of apoptotic cells was determined using flow cytometric analysis of PC9, A549, and H1299 cells transfected with siRNA for YTHDF1, YTHDF2, or siNC. Percentages of apoptotic cells are shown in a representative scatter plot. The apoptosis rates in cells with YTHDF1 or YTHDF2 knockdown were compared to those transfected with siNC and shown as a bar chart (n = 3, **P < .01 and ****P < .0001, Mann–Whitney U test). Results were presented as means ± SD.
Figure 5. YTHDF1 and YTHDF2 knockdown suppresses cell proliferation and partially induces apoptosis in lung cancer cells

Figure 6. YTHDF1 and YTHDF2 knockdown increased tumoral PD-L1 expression in lung cancer cells

(a) Venn diagram indicating the number of common genes in different sequences of siRNA at least 2.0-fold alteration of RNA expression (n = 1). (b) Representative immunoblot analysis of YTHDF1 and YTHDF knockdown lung cancer cells. The protein expression of YTHDF1 or YTHDF2 and PD-L1 and GAPDH were shown. The score below the photo is a quantification of the relative intensity of the PD-L1 band to GAPDH. (c) PD-L1 cell surface expression in PC9 cells with YTHDF1 or YTHDF2 knockdown with or without interferon-γ stimulation determined by flow cytometric analysis (n = 3 per group, ****P < .0001, Student’s t test). Results were presented as means ± SD.
Figure 6. YTHDF1 and YTHDF2 knockdown increased tumoral PD-L1 expression in lung cancer cells
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All data and supplemental information within the article are available from the corresponding author upon reasonable request.

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