Abstract
Nuclear factor of activated T cells 1 (NFATc1) is a transcription factor activated by T-cell receptor (TCR) and Ca2+ signaling that affects T-cell activation and effector function. Upon tumor antigen challenge, TCR and calcium-release-activated channels are induced, promoting NFAT dephosphorylation and translocation into the nucleus. In this study, we report a progressive decrease of NFATc1 in lung tumor tissue and in tumor-infiltrating lymphocytes (TIL) of patients suffering from advanced-stage non-small cell lung cancer (NSCLC). Mice harboring conditionally inactivated NFATc1 in T cells (NFATc1ΔCD4) 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. We found a reduction of effector memory and CD103+ tissue-resident memory (TRM) T cells in the lung of tumor-bearing NFATc1ΔCD4 mice, underlining an impaired cytotoxic T-cell response and a reduced TRM tissue-homing capacity. In CD4+ICOS+ T cells, programmed cell death 1 (PD-1) was induced in the draining lymph nodes of these mice and associated with lung tumor cell growth. 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. 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.Significance: The multifaceted role of NFATc1 in the activation and function of T cells during lung cancer development makes it a critical participant in antitumor immune responses in patients with NSCLC. Cancer Res; 78(13); 3619-33. ©2018 AACR.
Highlights
Nuclear factor of activated T cells is a transcription factor family that consists of five members, among which, NFAT1–4 (NFATc1– NFATc4) are regulated by Ca2þ–calcineurin signaling
We started to investigate the role of Nuclear factor of activated T cells 1 (NFATc1) in non–small cell lung cancer (NSCLC) by analyzing its mRNA expression in the tumoral (TU, solid tumor), peritumoral (PT, 2 cm around the solid tumor) and control lung region (CTR, tumor-free control area) of our cohort of patients with lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SCC), collectively grouped as NSCLC (Table 1)
We demonstrated an important function of NFATc1 for successful T-cell–mediated antitumoral immune responses in the setting of NSCLC
Summary
Nuclear factor of activated T cells is a transcription factor family that consists of five members, among which, NFAT1–4 (NFATc1– NFATc4) are regulated by Ca2þ–calcineurin signaling. NAFTc1 and NFATc2 are the main isoforms expressed in T cells critical in regulating early gene transcription in response to T-cell receptor (TCR)-mediated signals [1,2,3]. In resting T cells, NFAT transcription factors are located in the cytosol in an inactive, phosphorylated state. Upon TCR stimulation, NFAT is activated by calcium flux released from the endoplasmic reticulum and the extracellular environment through store-operated channels. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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