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. 2022 Aug 5:12:922899.
doi: 10.3389/fonc.2022.922899. eCollection 2022.

PD-L1 expression, tumor mutational burden, and immune cell infiltration in non-small cell lung cancer patients with epithelial growth factor receptor mutations

Tiantian Ma  1 , Jin Jiao  1 , Ran Huo  1 , Xiaofang Li  1 , Guotao Fang  1 , Qi Zhao  1 , Weiwei Liu  1 , Xiao Han  1 , Chenglin Xi  1 , Yanan Wang  2 , Yanhong Shang  1
Affiliations

PD-L1 expression, tumor mutational burden, and immune cell infiltration in non-small cell lung cancer patients with epithelial growth factor receptor mutations

Tiantian Ma et al. Front Oncol. .

Abstract

Background: Immunotherapy using programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors seems less effective in non-small cell lung cancer (NSCLC) patients with epithelial growth factor receptor (EGFR) mutations. Varied responses to PD-1/PD-L1 inhibitors have recently been observed in NSCLC patients harboring different types of EGFR mutations. Some EGFR-mutated NSCLC patients may benefit from PD-1/PD-L1 inhibitors. At present, PD-L1 expression, tumor mutational burden (TMB), and tumor immune microenvironment (TIME) are biomarkers for predicting the efficacy of PD-1/PD-L1 inhibitors in NSCLC patients. We retrospectively evaluated PD-L1 expression, TMB, and immune cell infiltration in NSCLC patients with EGFR mutation subtypes.

Methods: PD-L1 expression, TMB, and the abundance of immune cell infiltration in NSCLC patients were evaluated in public databases and clinical samples. TMB was detected using the NGS technique, PD-L1 was detected using immunohistochemistry, and the abundance of immune cell infiltration in NSCLC samples was detected using multiple immunohistochemistry.

Results: PD-L1 expression and TMB were lower in EGFR-mutated NSCLCs than in wild-type patients. Differences in the abundance of immune cell infiltration were also observed between EGFR-mutated and wild-type NSCLC. The expression of PD-L1, TMB, and abundance of immune cell infiltration were different in patients harboring different subtypes of EGFR mutations. Patients with uncommon EGFR mutations, especially the G719X mutation, showed higher TMB and expressions of PD-L1 than classical EGFR mutations. M1 macrophages were higher in uncommon EGFR mutations than classical EGFR mutations.

Conclusions: The expression of PD-L1 and TMB in uncommon EGFR-mutated NSCLCs, especially the G719X mutation, were higher than those for classical EGFR-mutated NSCLCs and similar to EGFR wild-type. The abundance of immune cell infiltration in uncommon EGFR-mutated NSCLCs was similar to that in EGFR wild-type. Our findings suggest that uncommon EGFR-mutated NSCLCs may benefit from PD-1/PD-L1 inhibitors.

Keywords: Epidermal growth factor receptor; Non-small cell lung cancer; Programmed death-ligand 1; Tumor immune microenvironment; Tumor mutational burden.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The proportion of patients with different subtypes of EGFR mutations in the 1,111 NSCLCs.
Figure 2
Figure 2
The expression of PD-L1 in TCGA database (A, B) and clinical center (C, D). (A) Comparison of PD-L1 expression in NSCLC patients from TCGA database between EGFR wild-type and EGFR-mutated groups. (B) Comparison of PD-L1 expression in NSCLC patients from TCGA database between EGFR classical mutations, uncommon mutations, and EGFR wild-type groups. (C) The expression of PD-L1 in patients with different EGFR mutations in our clinical center. (D) The distribution of PD-L1-/TMB-L, PD-L1-/TMB-H, PD-L1+/TMB-L, and PD-L1+/TMB-H in NSCLC patients with different EGFR mutations in our clinical center.
Figure 3
Figure 3
TMB in TCGA database (A, B) and clinical center (C). (A) Comparison of TMB in NSCLC patients from TCGA database between EGFR wild-type and EGFR-mutated groups. (B) Comparison of TMB in NSCLC patients from TCGA database between EGFR classical mutations, uncommon mutations, and EGFR wild-type groups. (C) The expression of TMB in patients with different EGFR mutations in our clinical center.
Figure 4
Figure 4
The co-mutation genetic alteration heatmap for different subtypes of EGFR mutations.
Figure 5
Figure 5
Immune cell infiltration in TCGA database. Comparison of immune cells in NSCLC patients from TCGA database between EGFR wild-type and EGFR-mutated groups (A), EGFR uncommon mutations and EGFR wild-type groups (B), EGFR classical mutations and EGFR wild-type groups (C), and EGFR classical mutations and uncommon mutations (D).
Figure 6
Figure 6
Immune cell infiltration in patients with classical EGFR mutations vs. uncommon EGFR mutations in clinical center data. (A) Comparison of immune cells in NSCLC patients from our clinical center between EGFR classical mutations and uncommon mutations. The infiltration of CD8 + PD1 + cells (B), CD3 + PD1 + cells (C), and CD3 + CD8 + cells (D) in patients with EGFR classical mutations and uncommon mutations.
Figure 7
Figure 7
PFS in EGFR-mutated NSCLC patients with different infiltrations of immune cells. Comparison of patient PFS between high and low infiltration of M1 macrophages (A), CD8 + T cells (B), CD3 + T cells (C), M2 macrophages (D), NK cells (E), CD3 + PD1 + T cells (F), CD3 + CD8 + T cells (G), and CD8 + PD1 + T cells (H).
Figure 8
Figure 8
Clinical response for third-line immunotherapy in a patient with uncommon type EGFR mutation.
See this image and copyright information in PMC

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