Prognostic Implications of Programmed Cell Death Ligand 1 Expression, Cluster of Differentiation 8-Positive T-Cell Infiltration, and Related Immunophenotypes in Invasive Mucinous Adenocarcinoma of the Lung: A Multicenter Study

Abstract

The immune microenvironment of invasive mucinous adenocarcinoma of the lung (IMA), a rare and heterogeneous subtype, remains poorly characterized, limiting insights into its potential response to immunotherapy. In this multicenter study, we systematically evaluated programmed cell death ligand 1 (PD-L1) expression (using tumor proportion score, TPS, and combined positive score, CPS) and cluster of differentiation 8-positive (CD8⁺) tumor-infiltrating lymphocyte (TIL) infiltration in the largest cohort to date of pathologically confirmed pure IMAs (n = 312), supported by single‑cell transcriptomic analysis. PD-L1 positivity was low (TPS≥1%: 9.0%; CPS≥1: 28.5%). While PD-L1 alone showed no prognostic significance, high CD8⁺ TIL percentage and density were independent, favorable prognostic factors for relapse-free survival, particularly in patients not receiving adjuvant therapy. By integrating TPS and CD8⁺ TIL percentage, we established a novel four-category immune phenotype classification that identified a distinct subgroup (Type IV: PD-L1⁺/CD8⁺) with significantly better outcomes. Preliminary analysis of 20 patients who received immune checkpoint inhibitors suggested that Type IV patients may derive greater clinical benefit. Single-cell RNA sequencing analyses revealed a paucity of effector CD8⁺ T cells in IMA. This work defines the unique immune landscape of IMA, introduces a clinically relevant immune phenotyping framework with prognostic and predictive potential, and provides a rationale for future immunotherapeutic strategies in this rare malignancy.

Keywords

cluster of differentiation 8 / immune phenotype / invasive mucinous adenocarcinoma of the lung, immune checkpoint / programmed cell death ligand 1 / rare malignancy

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