Keratinocyte differentiation antigen-specific T cells in immune checkpoint inhibitor-treated NSCLC patients are associated with improved survival

Oncoimmunology. 2021 Nov 27;10(1):2006893. doi: 10.1080/2162402X.2021.2006893. eCollection 2021.


Immune checkpoint inhibitors (ICIs) have improved the survival of patients with non-small cell lung cancer (NSCLC) by reinvigorating tumor-specific T cell responses. However, the specificity of such T cells and the human leukocyte antigen (HLA)-associated epitopes recognized, remain elusive. In this study, we identified NSCLC T cell epitopes of recently described NSCLC-associated antigens, termed keratinocyte differentiation antigens. Epitopes of these antigens were presented by HLA-A 03:01 and HLA-C 04:01 and were associated with responses to ICI therapy. Patients with CD8+ T cell responses to these epitopes had improved overall and progression-free survival. T cells specific for such epitopes could eliminate HLA class I-matched NSCLC cells ex vivo and were enriched in patient lung tumors. The identification of novel lung cancer HLA-associated epitopes that correlate with improved ICI-dependent treatment outcomes suggests that keratinocyte-specific proteins are important tumor-associated antigens in NSCLC. These findings improve our understanding of the mechanisms of ICI therapy and may help support the development of vaccination strategies to improve ICI-based treatment of these tumors.

Keywords: Immune checkpoint inhibitor therapy; NSCLC; autoimmune toxicity; tumor-associated antigen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Differentiation / therapeutic use
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Humans
  • Immune Checkpoint Inhibitors
  • Keratinocytes
  • Lung Neoplasms* / drug therapy


  • Antigens, Differentiation
  • Immune Checkpoint Inhibitors

Grants and funding

This project received funding from the Swiss National Science Foundation (PP00P3_157448), Swiss Cancer League (KLS-4409-02-2018), the Forschungsförderung of the Kantonsspital St.Gallen, and Novartis Foundation. L. F. discloses advisory roles for Novartis, Sanofi and Bristol-Myers Squibb. OHA is supported by a Swiss National Science Foundation grant (PMP400PM_194473).