Lack of CD8⁺ T cell effector differentiation during priming mediates checkpoint blockade resistance in non-small cell lung cancer

In non–small cell lung cancer (NSCLC), response to immune checkpoint blockade (ICB) is associated with programmed cell death ligand 1 expression that is induced by interferon-γ–producing, tumor-infiltrating CD8⁺ T cells. However, not all tumors with a CD8⁺ T cell infiltrate respond to ICB, and little is known about the mechanisms governing ICB resistance in T cell–infiltrated NSCLC. We used an orthotopic NSCLC mouse model to study ICB-refractory CD8⁺ T cell responses. Single-cell RNA sequencing of the NSCLC mouse tumors revealed that lung cancer–specific tumor-infiltrating CD8⁺ T cells exhibited clonal expansion but lacked expression of genes associated with effector and exhausted T cell responses, indicating that they underwent a differentiation program distinct from conventional T cell exhaustion. This lung cancer–specific T cell dysfunction program was established early during priming in the mediastinal lymph node and was characterized by robust proliferation but a failed up-regulation of effector and exhausted T cell characteristics. Intriguingly, CD8⁺ T cells from patients with NSCLC expressed an analogous gene expression program, which appeared distinct from conventional T cell exhaustion. Administration of recombinant interleukin-2 (IL-2) and IL-12 was sufficient to restore effector T cell differentiation and induce control of KP lung tumors. These findings imply that a CD8⁺ T cell differentiation trajectory, activated during T cell priming in the mediastinal lymph node, limits the response of CD8⁺ T cells to ICB and thereby may contribute to failure of ICB in a subset T cell–infiltrated NSCLC.