A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• The mechanisms of response and resistance to immune checkpoint blockers (ICBs) in cancer are not fully understood.
• Intratumoral T-cells and the tumor genomic landscape are critical factors influencing ICB efficacy.

Purpose of the Study:

• To investigate the relationship between intratumoral T-cells, tumor genomics, and response to PD-1 axis blockers in non-small cell lung carcinoma (NSCLC).
• To identify biomarkers predictive of response and survival in NSCLC patients treated with ICBs.

Main Methods:

• Paired whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) were performed on pre-treatment NSCLC samples.
• QIF measured CD3+ tumor infiltrating lymphocytes (TILs), T-cell proliferation (Ki-67), and effector function (Granzyme-B).
• Genomic data and QIF markers were correlated with clinical response and survival outcomes.

Main Results:

• Higher tumor mutational burden, neoantigen load, and intratumoral CD3+ T-cell levels were associated with favorable responses to PD-1 blockade.
• A distinct "dormant" TIL signature (elevated TILs with low proliferation/activation) correlated with survival benefits.
• Dormant TILs demonstrated potential for reactivation upon PD-1 blockade in a preclinical model.

Conclusions:

• Tumor genomics and specific intratumoral T-cell characteristics are significant determinants of response to immune checkpoint inhibitors in NSCLC.
• The "dormant" TIL signature represents a potentially targetable state for enhancing ICB therapy efficacy.
• Further research into T-cell dormancy and reactivation could lead to improved treatment strategies for NSCLC.