Abstract
Tumor metastases to regional lymph nodes are associated with worse outcome for patients with resected non-small cell lung cancer (NSCLC), but there is a wide variation in survival. We hypothesized that infiltration of tumor-involved lymph nodes with activated effector T cells would impact subsequent outcome. A total of 54 lymph nodes (27 N+ and 15 N- collected from 12 patients with Stage IIB (T2N1M0) and 12 N- lymph nodes collected from 10 patients with Stage IIA (T2N0M0) who underwent lymphadenectomy during surgical management of their NSCLC) were analyzed for effector T cells expressing activation markers PD-1 and TIM-3 using the Opal-multiple immunofluorescence assay. The frequency of CD3+CD8+ (P=0.0001), CD3+CD8+TIM-3+ (P<0.0001), and CD3+CD8+TIM-3+Ki-67+ (P<0.0001) T cells was greater in lymph nodes of IIA patients compared with IIB patients; however the frequency of CD3+CD8+PD-1+ (P=0.0086), CD3+CD8+TIM-3+ (P=0.0129), CD3+CD8+PD-1+Ki-67+ (P<0.0001) and CD3+CD8+TIM-3+Ki-67+ (P=0.0001) T cells was greater among the tumor involved (N+) nodes of N1 patients compared with the tumor-uninvolved (N-) nodes. The frequency of intranodal CD3+CD8+, CD3+CD8+PD-1+ and CD3+CD8+PD-1+Ki-67+ T cells in N+ nodes was associated with prolonged progression-free (PFS) and overall survival (OS). These data suggest that CD3+CD8+TIM-3+ T cells may suppress tumor spread to regional lymph nodes but once tumor cells metastasize to lymph nodes, CD3+/CD8+/PD-1+/Ki67+ T cells localizing to N+ nodes may prevent further tumor spread, resulting in prolonged survival.