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

Abstract

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 ICBrefractory 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.