Impact of Stress-Induced Steroid Secretion on outcome of Immunotherapy in patients with lung cancer: the SISSI study

In recent years, immunotherapy based on the induction of host immune response through the use of immune checkpoint inhibitors (ICIs) has completely changed the management of several cancers [1]. The long-term benefit of ICIs has been demonstrated in non-small cell lung cancer (NSCLC), even attaining a complete response in selected patients with metastatic disease [2]. However, the efficacy is not universal and a large number of patients fails to achieve a clinical response [3]. Although predictive factors of response have not been clearly identified, it is conceivable that an excess of glucocorticoids (GCs) could limit ICI efficacy due to the well-known GC-related immune suppressive action. Studies demonstrated that administration of high doses of GCs is associated with adverse outcomes in patients with ICI-treated NSCLC [4, 5]. Moreover, trials including patients with adrenocortical cancer treated with ICIs found that patients with tumors actively secreting cortisol had a lower likelihood to respond [6, 7]. Since GCs are the key “stress hormones”, it is conceivable that abnormalities in the hypothalamic–pituitary–adrenal (HPA) axis are present in several patients with advanced cancer, who live in a condition of chronic stress. Emotional distress has been reported in 46%, anxiety in 35% and depression in 31% of patients with advanced lung cancer [8]. Interestingly, a correlation has been found between worse scores in questionnaires evaluating psychological distress and lower efficacy of immunotherapy in patients with advanced NSCLC [9]. Despite growing evidence that chronic stress is associated with increased risk of cancer mortality, the causal mechanisms between stress and cancer have not yet fully understood [10]. However, several observations lead to suppose that the disturbance of the HPA axis could represent a link. First, loss of the circadian cortisol rhythm and reduced response to dexamethasone suppression have been associated with earlier mortality for several cancers [11-14]. Second, a recent study demonstrated that high GC levels due to chronic stress caused neutrophil-mediated changes in the lung microenvironment, promoting metastases in mice with breast cancer. Furthermore, the study showed that chronic stress failed to induce metastases in mice with deletion of the neutrophil-specific GC receptors [15]. There is additional evidence that the stress-induced increase in GCs has a potent immunosuppressive effect through the upregulation of the glucocorticoid-inducible factor Tsc22d3, causing the failure of immunogenic chemotherapy with oxaliplatin or anthracyclines. Conversely, the use of mifepristone, an antagonist of the GC receptor, restored the efficacy of treatment in mice [16]. Interestingly, preliminary data suggest that the mindfulness-based stress reduction (MBSR) improves the alteration of HPA axis in patient with cancer [17]. Given the potential of the MBSR to reduce psychological stress and to target molecular pathways that correlate with a worse prognosis in cancer, using MBSR as an intervention to ameliorate quality of life and to prolong survival in patients with cancer appears quite attractive [18]. Despite this interesting background, a comprehensive evaluation of the HPA axis in patients with immunotherapytreated cancers is still lacking. These issues remain unclarified: i) what is the correlation between the altered function of the HPA axis and self-reported measures of psychological stress; ii) what is the association between the altered function of the HPA axis and treatment outcome; iii) what is the effect of MBSR on the HPA axis; iv) what is the effect of MBSR on survival in patients receiving ICIs for advanced lung cancer.