Prognostic value of tumor-infiltrating lymphocytes for patients with completely resected stage IIIA(N2) non-small cell lung cancer

Abstract

Background: The patient prognosis after complete resection for pathologic stage IIIA(N2) non-small cell lung cancer (NSCLC) remains a significant concern. The clinical relevance of the host immune response to NSCLC has yet to be established. We aimed to investigate the prognostic value of tumor-infiltrating lymphocytes (TILs) in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC.

Methods: From 2005 to 2012, consecutive patients with pathologic stage IIIA(N2) NSCLC who underwent complete resection at our institution were reviewed. For each case, full-face hematoxylin and eosin-stained sections from surgical specimens were evaluated for the TIL density. A published, recommended TIL scoring scale was followed. The patients were stratified into the TIL- or TIL+ group based on pathologic evaluation.

Results: Data from 320 patients were included in the analysis. Based on a median follow-up duration of 30.8 months, a higher density of TILs was associated with an improved postoperative survival time (P = 0.06). Subgroup analyses indicated that this positive effect was the greatest for patients with squamous cell carcinoma (SCC; P = 0.03). Among those with SCC, the TIL+ patients experienced a significantly increased 3-year distant metastasis-free survival (DMFS) compared to the TIL- patients (60.6% versus 42.7%, P = 0.02). Multivariate analyses of the 93 patients with SCC tumors confirmed that TIL+ was an independent prognostic factor for an increased DMFS (HR = 0.39, 95%CI 0.17-0.87, P = 0.02) and a prolonged overall survival (OS; HR = 0.47, 95%CI 0.22-1.00, P = 0.05).

Conclusions: Our data suggest a potential role of TILs in predicting the survival of patients with completely resected stage IIIA(N2) NSCLC. The beneficial effects of TILs were more pronounced in the prediction of the DMFS and the OS in patients with SCC. This parameter should be considered for prospective inclusion in clinical trials.

Keywords: lymphocytic infiltration; non-small cell lung cancer; prognosis; survival; tumor-infiltrating lymphocytes.

Figure 1

(A) Plot of the LRFS for all patients stratified into TIL groups; (B) Plot of the DMFS for all patients stratified into TIL groups. Abbreviations: LRFS = locoregional recurrence free survival; DMFS = distant metastasis free survival; TIL = tumor-infiltrating lymphocyte.

Figure 2

(A) Plot of the OS for all patients stratified into TIL groups; (B) Subgroup analyses of the OS according to each clinicopathological characteristic. Abbreviations: OS = overall survival; TIL = tumor-infiltrating lymphocyte; SCC = squamouscell carcinoma; ALI = angiolymphatic invasion; CI = confidence interval.

Figure 3

(A) Plot of the LRFS for patients with the SCC histological type stratified into TIL groups; (B) Plot of the DMFS for patients with the SCC histological type stratified into TIL groups; (C) Plot of the OS for patients with the SCC histological type stratified into TIL groups. Abbreviations: LRFS = locoregional recurrence free survival; DMFS = distant metastasis free survival; OS = overall survival; SCC = squamous cell carcinoma; TIL = tumor-infiltrating lymphocyte.

Figure 4

(A) TIL− group (score 0): almost no lymphocyte infiltration into the stroma of surrounding cancer nests; (B) TIL− group (score 1): low lymphocyte infiltration into the stroma of surrounding cancer nests; (C) TIL+ group (score 2): moderate lymphocyte infiltration into the stroma without tumor nest permeation; and (D) TIL+ group (score 3): intense lymphocyte infiltration into the stroma and insertion between tumor cells. (100X magnification, H & E-stained sections). Abbreviations: TIL = tumor-infiltrating lymphocyte.