DSTYK inhibition increases the sensitivity of lung cancer cells to T cell–mediated cytotoxicity

Abstract

Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α–mediated CD8+-killing and immune-resistant lung tumors to anti–PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.

Eating away T cell responses in lung cancer

“…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.…”

“…Autophagy inhibition in LKB1 mutant NSCLC restores HLA-mediated antigen presentation and effector T cell expansion ( Deng et al, 2021 ). Although no data are reported in the article by Valencia et al (2022) , the increased CD8 + T cell killing of DSTYK KO cells could be explained also by an increased HLA expression upon autophagy inhibition. In this regard, HLA loss of heterozygosis (detected in up to 30% of NSCLC) has been reported to influence the impact of tumor mutational burden as a predictor of response to ICI ( Shim et al, 2020 ); therefore, correlation between HLA expression and DSTYK CNG would probably deserve further research.…”

“…In this evolving scenario, DSTYK is described by Valencia et al (2022) as a key cancer cell–intrinsic protecting hub which mediates tumor immune escape, inducing autophagy and oxidative stress response.…”

“…In an article by Valencia et al (2022) in this issue of JEM , mutations or copy number gains (CNG; three or more copies) of DSTYK are observed in 6.4% of lung cancer samples included in The Cancer Genome Atlas dataset, and CNG is also detected in 13.3% of 45 frozen NSCLC samples from a single institution. Importantly, CNG correlates with increased DSTYK expression and poor prognosis.…”

“…Use of ICI (2) allows T cell activation and production of effector molecules including TNF-α (3). Valencia et al (2022) show that in DSTYK low 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).…”