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Editorial
. 2022 Dec 5;219(12):e20221449.
doi: 10.1084/jem.20221449. Epub 2022 Oct 10.

Eating away T cell responses in lung cancer

Roberto Ferrara  1 , Luca Roz  2
Affiliations
Editorial

Eating away T cell responses in lung cancer

Roberto Ferrara et al. J Exp Med. .

Abstract

Despite evidence for clinical benefit in patients suffering from lung cancer following treatment with immune checkpoint inhibitors (ICI), it is still uncertain how to predict which patients are likely to experience a significant response. In their work, Valencia et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20220726) identify the DSTYK kinase as a cancer cell-intrinsic modulator of response to immunotherapy. Through regulation of the mTOR pathway and stimulation of protective autophagy, DSTYK blunts CD8+ T cell-mediated killing of cancer cells. Accordingly, lung cancers with increased expression of DSTYK are less responsive to ICI treatment. These observations could be useful in the clinic towards the development of predictive biomarkers and novel therapeutic strategies.

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Figures

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Insights from Roberto Ferrara and Luca Roz.
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Figure 1. DSTYK protects cancer cells from oxidative stress and TNF-α–mediated CD8+ T cell killing. Tumor antigens presented on MHC complexes are recognized by CD8+ cells through interaction with the T cell receptor. T cell responses can be negatively regulated by immune checkpoints, including the PD-1/PD-L1 axis (1). Use of ICI (2) allows T cell activation and production of effector molecules including TNF-α (3). Valencia et al. (2022) show that in DSTYKlow cells (left), autophagic activity is low, resulting in oxidative stress, accumulation of damaged mitochondria, and activation of TNF-α–mediated apoptosis and necroptosis (4). When DSTYK is expressed at high levels (right), its inhibitory function on the mTOR pathway favors activation of protective autophagy, resulting in reduction of oxidative stress damage and resistance to T cell–mediated cell killing (5). Figure created with BioRender.com.
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Figure 2. Tumor-intrinsic and -extrinsic mechanisms of resistance to ICI in NSCLC with cellular stress vulnerabilities. Different mechanisms have been identified as drivers of resistance to ICI therapy in NSCLC with genetically determined stress vulnerabilities, ranging from HLA downregulation to T cell exclusion. Valencia et al. (2022) provide evidence that NSCLC with high expression of DSTYK escape T cell killing through autophagy and protection from ROS-induced mitochondrial damage. On the contrary, there is apparently no effect of DSTYK in T cell recruitment, while potential regulation of antigen presentation or generation of immunosuppressive local and systemic microenvironments remains to be investigated.
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