The role of NFATc1 in T cell-mediated immune responses during the development of lung cancer

Main Article Content

Lisanne Heim
Juliane Friedrich
Marina Engelhardt
Denis I. Trufa
Carol I. Geppert
Ralf J. Rieker
Horia Sirbu
Susetta Finotto


Purpose/Objectives: NFATc1 (nuclear factor of activated T cells 1) belongs to the NFAT family of transcription factors and regulates T cell activation as well as effector and cytotoxic T cell functions in many tissues. In most of the established tumors, inhibitory receptors like programmed cell death protein 1 (PD-1) contribute to the functional impairment of T cell activation by persistent tumour antigen challenge, a process that is called T cell exhaustion. Cancer immunotherapies are aimed to reawake exhausted T cells by blocking inhibitory checkpoint receptors or immunosuppressive cells. As NFATc1 is important for T cell activation we asked whether this factor could be important for the reactivation of exhausted T cells in non-small cell lung cancer (NSCLC).

Materials/Methods: We analyzed NFATc1 and its interplay with PD-1 in a human NSCLC patient cohort using qPCR, IHC and FACS. Furthermore, in a murine model of lung adenocarcinoma, we determined lung tumour growth in mice with a conditional inactivation of NFATc1 in T cells (NFATc1ΔCD4) and analyzed the influence of anti-PD-1 antibody treatment on NFATc1 protein levels in T cells of lung-tumour bearing wild-type mice.

Results and Conclusion: In this study, we report a progressive decrease of NFATc1 in lung tumor tissue and in tumor-infiltrating lymphocytes (TIL) of patients suffering from advancedstage NSCLC. NFATc1ΔCD4 mice showed increased lung tumor growth associated with impaired T-cell activation and function. Furthermore, in the absence of NFATc1, reduced IL2 influenced the development of memory CD8+ T cells. Specifically, we discovered a reduction in effector memory and CD103+ tissue-resident memory (TRM) CD8+ T cell numbers in the lung of tumor-bearing NFATc1ΔCD4, underlining an impaired cytotoxic T-cell response and a reduced TRM tissue-homing capacity. Targeting PD-1 resulted in NFATc1 induction in CD4+
and CD8+ T cells in tumor-bearing mice and was associated with increased antitumor cytotoxic functions. Thus this study reveals a role of NFATc1 in the activation and cytotoxic functions of T cells, in the development of memory CD8+ T-cell subsets, and in the regulation of T-cell exhaustion. These data underline the indispensability of NFATc1 for successful antitumor immune responses in patients with NSCLC.

Article Details

Section 8: Immunomodulation / Tumor Biology