Identification of Potential Prognostic and Predictive Immunological Biomarkers in Patients with Stage I and Stage III Non-Small Cell Lung Cancer (NSCLC): A Prospective Exploratory Study

Abstract

Radiotherapy (RT) and chemotherapy can induce immune responses, but not much is known regarding treatment-induced immune changes in patients. This exploratory study aimed to identify potential prognostic and predictive immune-related proteins associated with progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC). In this prospective study, patients with stage I NSCLC treated with stereotactic body radiation therapy (n = 26) and patients with stage III NSCLC treated with concurrent chemoradiotherapy (n = 18) were included. Blood samples were collected before (v1), during (v2), and after RT (v3). In patients with stage I NSCLC, CD244 (HR: 10.2, 95% CI: 1.8–57.4) was identified as a negative prognostic biomarker. In patients with stage III NSCLC, CR2 and IFNGR2 were identified as positive prognostic biomarkers (CR2, HR: 0.00, 95% CI: 0.00–0.12; IFNGR2, HR: 0.04, 95% CI: 0.00–0.46). In addition, analysis of the treatment-induced changes of circulating protein levels over time (Δv2/v3−v1) also identified CXCL10 and IL-10 as negative predictive biomarkers (CXCL10, HR: 3.86, 95% CI: 1.0–14.7; IL-10, HR: 16.92 (2.74–104.36)), although serum-induced interferon (IFN) response was a positive prognostic. In conclusion, we identified several circulating immunogenic proteins that are correlated with PFS in patients with stage I and stage III NSCLC before and during treatment.

Analysis of Clinical Implications and Immune Landscape in Prognostic Model based on Immune Cell Signatures for Lung Adenocarcinoma Patients

“…As an immune-related gene, MS4A1 was used to predict the prognosis of LURD patients whose dysregulation in interstitial lymphocytes may contribute to the progression of LURD 41,42 . In addition, a prospective exploratory study in patients with stage III NSCLC has shown that CR2 was identi ed as a positive prognostic biomarker which was highly correlated with PFS of patients 43 . What's more, Baglivo S. etc.…”

Immunotherapy in unresectable stage III non-small-cell lung cancer: state of the art and novel therapeutic approaches

“…Frailer patients are more prone to develop toxicities during CRT, and we can speculate that their immune system might be more severely impaired by CRT jeopardizing immunotherapy efficacy. 18 Based on the aforementioned trials and biological evidence, fit patients treated with SCRT might derive meaningful survival benefit from adjuvant immunotherapy, although data for patients with PS ¼ 2 are largely lacking. Studies should be carried out in this patients' population, as well.…”

“…The main perk of this approach is to engage with a healthy immune system, not impaired by chemotherapy and radiotherapy, as could be the case in an adjuvant approach. 18 Preclinically, a more robust activation of the immune system translated in more effective immune surveillance against micrometastatic disease. 62 An intact tumor itself might imply more neoantigens for priming the immune system.…”

“…119 Both SBRT and RT result in neoantigen production and higher expression of calreticulin on the tumor cell surface, enhancing T-cell activation. 18,120 SBRT increases non-synonymous mutation inducing tumor-specific neoantigen development. 116 SBRT promotes the expression of major histocompatibility complex (MHC) class 1 and of immunogenic cell surface markers such as ICAM-1 and Fas, and increases the diversity of T-cell receptor repertoire in the TME.…”

A first-in-class, non-invasive, immunodynamic biomarker approach for precision immuno-oncology

“…For example, our assay showed that non-small cell lung carcinoma (NSCLC) patients treated with stereotactic body radiation therapy (SBRT) had elevated plasma-induced IFN/ISG response activity after treatment, associating with significantly better PFS. 10 …”