Female Gender Predicts Augmented Immune Infiltration in Lung Adenocarcinoma

Clin Lung Cancer. 2021 May;22(3):e415-e424. doi: 10.1016/j.cllc.2020.06.003. Epub 2020 Jun 14.


Introduction: Immune infiltration in lung adenocarcinomas (LUADs) has been associated with response to immune checkpoint inhibitors. Clinical features underlying differential responses of patients with LUADs to immunotherapy are not well understood. Here, we analyzed the association between LUAD immune infiltration and clinicopathologic variables.

Materials and methods: Intratumoral CD3, CD8, and CD68 cell densities (tumor-associated immune cells [TAICs]) were immunohistochemically assessed in 146 surgically resected LUADs. LUADs were classified into 2 groups, low and high TAICs, based on the median values of cell densities for CD3, CD8, and CD68. Somatic mutation burden and driver gene mutation status were analyzed in a subset of the cases (n = 92). We statistically analyzed the association between the TAIC groups and various clinicopathologic and molecular variables by using the χ2/Fisher and Wilcoxon sum tests and multivariable logistic regression models.

Results: Patient gender, tumor size, and STK11 mutations were significantly associated with TAIC levels in LUAD. Female patients exhibited significantly elevated TAIC levels (P = .005) compared with male patients. Tumor size was inversely associated with TAIC levels (P = .012). STK11 mutated tumors were associated with lower TAICs (P = .008). Higher TAICs were consistently observed in female patients with LUADs after adjusting for stage, tumor size, and age. Multivariable regression models confirmed female gender as an independent variable associated with TAIC levels in LUAD (P = .0141).

Conclusion: Immune infiltration in LUADs was significantly higher in female patients, warranting further exploration into the association between this clinical variable and immunotherapeutic response in LUAD.

Keywords: CD3; CD68; CD8; Gender disparity; Tumor immune infiltration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases / genetics
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / immunology
  • Adenocarcinoma of Lung / therapy*
  • Adult
  • Aged
  • Aged, 80 and over
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / administration & dosage
  • Immune Checkpoint Inhibitors / pharmacology
  • Immunotherapy / methods*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology
  • Lung Neoplasms / therapy*
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Staging
  • Retrospective Studies
  • Sex Factors
  • Treatment Outcome


  • Immune Checkpoint Inhibitors
  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases