Dysfunction of CD8 T cells around tumor cells leads to occult lymph node metastasis in NSCLC patients.

Occult lymph node metastasis (OLNM) is one of the main causes of regional recurrence in inoperable N non-small cell lung cancer (NSCLC) patients following stereotactic ablation body radiotherapy (SABR) treatment. The integration of immunotherapy and SABR (I-SABR) has shown preliminary efficiency in mitigating this recurrence. Therefore, it is necessary to explore the functional dynamics of critical immune effectors, particularly CD8 T cells in the development of OLNM. In this study, tissue microarrays (TMAs) and multiplex immunofluorescence (mIF) were used to identify CD8 T cells and functional subsets (cytotoxic CD8 T cells/predysfunctional CD8 T cells (CD8 T)/dysfunctional CD8 T cells (CD8 T)/other CD8 T cells) among the no lymph node metastasis, OLNM, and clinically evident lymph node metastasis (CLNM) groups. As the degree of lymph node metastasis escalated, the density of total CD8 T cells and CD8 T cells, as well as their proximity to tumor cells, increased progressively and remarkably in the invasive margin (IM). In the tumor center (TC), both the density and proximity of CD8 T cells to tumor cells notably decreased in the OLNM group compared with the group without metastasis. Furthermore, positive correlations were found between the dysfunction of CD8 T cells and HIF-1αCD8 and cancer microvessels (CMVs). In conclusion, the deterioration in CD8 T cell function and interactive dynamics between CD8 T cells and tumor cells play a vital role in the development of OLNM in NSCLC. Strategies aimed at improving hypoxia or targeting CMVs could potentially enhance the efficacy of I-SABR.