The germline HLA-A02B62 supertype is associated with a PD-L1-positive tumour immune microenvironment and poor prognosis in stage I lung cancer

Abstract

Background

Germline HLA class I molecule supertypes are shown to correlate with response to anti-PD-1 therapy. Here, we investigate the significance of germline HLA-A and HLA-B supertypes in tumour microenvironment of non-small-cell lung cancer.

Methods

Totally 278 NSCLC patients were collected retrospectively. HLA genotyping was conducted using next-generation sequencing. The evaluation of tumour-infiltrating lymphocytes was performed by multiplex immunohistochemistry assay. Correlations among HLA supertypes, tumour infiltrating lymphocytes, and clinicopathological characteristics were assessed.

Results

HLA-A03 and HLA-B62 were the supertypes with the highest proportions, at 69.1% and 52.2%, respectively. HLA-A02 or HLA-B62, but not HLA-A03, associated with higher PD-L1 ⁺ tumour and stromal cells levels, CD68 ⁺ cells, and CD68 ⁺PD-L1 ⁺ cells. Patients with both HLA-A02 and HLA-B62 supertypes displayed significantly higher PD-L1 ⁺ cells, CD68 ⁺ cells, and CD8 ⁺ cells levels than patients with other supertypes ( P = 0.0301, P = 0.0479, P = 0.0192). These cells collectively constitute a hot but immunosuppressive tumour microenvironment. Accordingly, patients with both HLA-A02 and HLA-B62 supertypes had short progression-free survival after surgery (HR = 2.27, P = 0.0373).

Conclusions

The HLA-A02B62 supertype could serve as a possible indicator of poor prognosis in early-stage lung cancer. However, it may also act as a favorable prognostic factor for immunotherapy, given its association with a PD-L1-positive tumour microenvironment.