Predictive Biomarkers for Checkpoint Inhibitor-Based Immunotherapy: The Galectin-3 Signature in NSCLCs

Abstract

Checkpoint inhibitor-based immunotherapy is opening a promising scenario in oncology, with objective responses registered in multiple cancer types. However, reliable predictive markers of tumor responsiveness are still lacking. These markers need to be urgently identified for a better selection of patients that can be candidates for immunotherapy. In this pilot study, a cohort of 34 consecutive patients bearing programmed death-ligand 1 (PD-L1)-positive non-small cell lung carcinoma (NSCLC), treated with pembrolizumab, was considered. The retrospective immuno-phenotypic analysis performed on the original tumor biopsies allowed for the identification of a specific "galectin signature", which strongly correlated with tumor responsiveness to anti PD-1 immunotherapy. We observed that the large majority of patients (about 90%) with high galectin-3 tumor expression (score 3+) showed an early and dramatic progression of the disease after three cycles of treatments. In contrast, all patients with negative or low/intermediate expression of galectin-3 in tumor cells showed an early and durable objective response to pembrolizumab, indicating galectin-3 as an interesting predictive marker of tumor responsiveness. The galectin-3 signature, at least in NSCLCs, promises a better selection of patient candidates for immunotherapy, reducing unnecessary treatment exposures and social costs. A large multicenter study is ongoing to validate this finding.

Keywords: checkpoint inhibitors; galectin-3; non-small cell lung carcinoma; pembrolizumab; predictive marker.

Figure 1

Galectin-3 expression in NSCLC biopsies. (a) Squamous cell carcinoma, galectin-3-negative. Note the expected expression of galectin-3 in normal bronchial epithelium at the bottom of the tumor, which represents the internal positive control (arrow). (b) High galectin-3-positive lung adeno-carcinoma (score 3+). (Magnification 250×; Immunoperoxidase staining as reported in the material and method section).

Figure 2

Spider plot of tumor response to checkpoint inhibitor therapy. The clinical response of each patient listed in Table 1 is plotted in this picture to better correlate galectin-3 expression with tumor sensitivity to pembrolizumab during follow-up. According to Table 1: patients with high galectin-3 expression (red lines), the large majority of which showed disease progression after 20 weeks of follow-up; patients with negative–low/intermediate galectin-3-expressing tumors (green lines) showing significant sensitivity to pembrolizumab. One patient had a complete response (n°4);