Spatial Localization of Tissue-Resident Memory T Cells in Non-Small Cell Lung Cancer

The spatial distribution of CD103+CD8+ tissue-resident memory T cells is a prognostic biomarker for non-small cell lung cancer, according to the results of a recent cohort study.

Tissue-resident memory T cells (T_RM) are a special population of immune cells that reside in solid[spacer height=”10px”]tumors and their microenvironment. Although emerging evidence has linked these cells to[spacer height=”20px”]better response to immunotherapy, their role is controversial, as the functional and spatial[spacer height=”20px”]heterogeneity of T_RM subsets remains unknown.

A study in the Journal of Translational Medicine determined the spatial localization of CD103+CD8+[spacer height=”20px”]T_RM subsets through multiplex immunofluorescence in non-small cell lung cancer (NSCLC) patients.

Study Population

A total of 274 patients with stage IA–IIIB NSCLC were enrolled, among whom 108 relapsed during[spacer height=”20px”]follow-up. The median follow-up period was 65.9 months. Most patients were male (65%), with stage[spacer height=”20px”]I disease (55.3%) and lung adenocarcinoma (65.3%).

CD103+CD8+ T_RM cells Exhibited Better Infiltration and Stronger Interaction With Cancer Cells

T_RM cells (CD103+CD8+ cells) accounted for more than half of the CD103+ cells in the tumor center[spacer height=”10px” id=”3″](TC) and the invasive margin (IM). T_RM cells predominated cytotoxic T cells (CD8+ cells) in TC, and vice[spacer height=”10px” id=”3″]versa in the IM. Compared to T_non-RM (CD8+CD103– cells), T_RM cells exhibited a higher infiltration score[spacer height=”10px” id=”3″]in TC, shorter mean nearest neighboring distance to cancer cells in TC and IM, and higher cancer cell[spacer height=”20px”]proximity score in the IM (all P<0.001), suggesting better infiltration and stronger interaction with[spacer height=”20px”]cancer cells of T_RM.

Diverse CD103+CD8+ T_RM Cells Correlated With Immune Checkpoints

CD103+CD8+ cells demonstrated a significant positive correlation with immune checkpoint[spacer height=”20px”]expression, i.e., PD-1+CD8+, Tim-3+CD8+, and with GZMB+CD8+ cells. Four T_RM subgroups were[spacer height=”10px” id=”3″]defined based on immune checkpoint expression patterns: T_RM1 (PD-1–Tim-3–T_RM1), T_RM2 (PD-1+Tim-3[spacer height=”10px” id=”3″]–T_RM), T_RM3 (PD-1–Tim-3+T_RM), and T_RM4 (PD-1+Tim-3+T_RM). The IM exhibited more T_RM1 and less T_RM4 [spacer height=”10px” id=”3″]than TC. The infiltration scores of  T_RM1 and T_RM2 were significantly lower than those of T_RM3 and T_RM4.[spacer height=”10px” id=”3″] The mean nearest neighboring distance to cancer cells progressively decreased, and the cancer-cell[spacer height=”20px”]proximity score progressively increased from T_RM1 to T_RM4.

T_RM Cell Subsets May Act as a Prognostic Biomarker for NSCLC Patients

For a comprehensive assessment of T_RM, T_RM-based spatial immune signature (T_RM-SIS) was[spacer height=”20px”]constructed by integrating multiple machine learning methods. The effectiveness of T_RM-SIS was[spacer height=”20px”]evaluated and validated through time-dependent receiver operating characteristic curve analyses.[spacer height=”20px”]The area under the curve values for 1-, 3-, and 5-year disease-free survival (DFS) were as follows:[spacer height=”20px”]0.823, 0.794, and 0.742, respectively, in the training set, 0.687, 0.691, and 0.690, respectively, in the[spacer height=”20px”]testing set, and 0.776, 0.730, and 0.693, respectively, in the entire cohort.

The T_RM-SIS system demonstrated better predictive capability than the TNM staging system. In[spacer height=”20px”]survival analyses, patients with high T_RM-SIS had a worse prognosis than those with low T_RM-SIS[spacer height=”20px”](mDFS: 33.07 months vs. not reached in the training set (P<0.001), 67.97 months vs. not reached in[spacer height=”20px”]the testing set (P=0.048), and 58.93 months vs. not reached in the entire cohort (P<0.001),[spacer height=”20px”]respectively). The T_RM-SIS emerged as an independent prognostic factor for DFS (hazard ratio=2.43,[spacer height=”20px”]95% confidence interval: 1.63–3.60, P<0.001).

Tumor Angiogenesis Was Found to Be Unfavorable to T_RM Cells

Gene set enrichment analysis showed that tumor angiogenesis impeded T_RM. Cancer microvessels[spacer height=”20px”](CMVs) were negatively correlated with T_RM density, infiltration score, and cancer cell proximity score[spacer height=”20px”]and positively correlated with the mean nearest neighboring distance from T_RM cells to cancer cells.[spacer height=”20px”]The high T_RM-SIS group showed a significantly higher CMV density in the IM than the low T_RM-SIS[spacer height=”20px”]group. High CMV density was associated with a poor NSCLC prognosis.

Source:

Yang, G., Cai, S., Hu, M., Li, C., Yang, L., Zhang, W., Sun, J., Sun, F., Xing, L., & Sun, X. (2024). Spatial features of specific CD103+CD8+ tissue-resident memory T cell subsets define the prognosis in patients with non-small cell lung cancer. Journal of Translational Medicine, 22(1). https://doi.org/10.1186/s12967-023-04839-4