Lung adenocarcinoma (LUAD), the most common type of lung cancer, has an average 5-year survival rate of 15%. In LUAD, interaction between tumor and immune cells has been shown to be highly associated with the likelihood of disease progression and metastases. We have previously demonstrated the association between spatial architecture and arrangement of tumor-infiltrating lymphocytes (TILs) with likelihood of recurrence in early stage NSCLC. Recently, gene set enrichment analysis-derived immune scores have been found to be prognostic of outcome. However, this requires transcriptomics techniques as a precursor, which involves mechanical disruption of cells and tissues. In this work (N = 170), we extracted graph-based histomorphometric features on segmented nuclei from digitized H and E biopsy images and then performed principal component analysis (PCA) to select the most representative tiles from each patient. We then identified TILs and quantitative histomorphometric attributes of different nuclei groups (all-nuclei, TILs, non-TILs) prognostic of overall patient survival (OS) and further investigated their associations with immune scores and biological pathways implicated immune response using gene-set enrichment analysis (GSEA). We found TIL-compactness (a set of TIL density features) derived risk scores were prognostic of OS (Hazard Ratio (HR) = 3.26, p = 0.012, C-index = 0.634). The median immune score (IS) in the cohort was used as a threshold to divide the cases into low and high IS expression groups. The TIL compactness measures prognostic of OS were also statistically significantly correlated with the IS and biological pathways related to immune response (Immune System Process, Immune Response, Adaptive Immune Response, and Humoral Immune Response Mediated by Circulating Immunoglobulin).
Immune checkpoint inhibitors targeting the programmed cell death (PD)1/ L1 axis have been approved for treatment of chemotherapy refractory advanced non-small cell lung cancer (NSCLC) for a few years. While higher PD-L1 expression is associated with better outcomes after monotherapy with immune checkpoint inhibitors, it is not a perfect predictive biomarker for clinical benefit from immunotherapy, because some patients with low PD-L1 expression have sustained responses. In clinical practice, using radiological tools like Response Evaluation Criteria in Solid Tumors (RECIST), tends to underestimate the benefit of therapy. For instance, some patients treated with immunotherapy suffer from pseudoprogression while actually having a favorable response, RECIST in this setting is inadequate to capture the response. In this study we sought to explore whether radiomic texture features extracted from both inside and outside of the tumor from baseline CT scans were associated with overall patient survival (OS) in 139 NSCLC patients being treated with IO from two separate sites. Patients were divided into a discovery (D1 = 50; nivolumab from Cleveland Clinic) and two validation sets (D2 = 62 from Cleveland Clinic, D3 = 27 from University of Pennsylvania Health System. Patients in the validation sets had been treated with different types of checkpoint inhibitor drugs including nivolumab, pembrolizumab, and atezolizumab. 454 radiomic texture features from within (intra-tumoral) and outside the tumor (peri-tumoral) were extracted from baseline contrast CT images. Following feature selection on the discovery set, a radiomic risk-score signature was generated by using least absolute shrinkage and selection operator. Using a Cox regression model, the association of the radiomic signature with overall survival (OS) was evaluated in the discovery and two validation sets. In addition, 95% confidence intervals (CI) and relative hazard ratios (HR) were calculated. Our results revealed that the radiomics signature was significantly associated with OS, both in the discovery set (HR = 5.06, 95%CI = 3, 8.55; p-value < 0.0001) and the two validation data sets (D2: HR = 5.88, 95% CI = 2.19, 21.63, p-value = 0.0009; D3: HR = 5.37, 95% CI = 1.74, 16.57, p-value = 0.0034). Our initial results appear to suggest that our radiomic signature could serve as a non-invasive way of predicting and monitoring response to checkpoint inhibitors for patients with non-small cell lung cancer.
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