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

Description A lung cancer–specific form of CD8+ T cell dysfunction is established during T cell priming and contributes to ICB resistance. A unique T cell subset in lung cancer Although some non–small cell lung cancers (NSCLC) are sensitive to immune checkpoint blockade (ICB), many patients with NSCLC do not respond to ICB, which may relate to the lack of infiltration of CD8+ T cells. Here, Horton et al. used mouse models of flank and lung tumors to show that CD8+ T cells from lung tumors, not flank tumors, had a dysfunctional phenotype distinct from conventional T cell exhaustion that was established in the draining lymph node and correlated to ICB resistance. IL-2 and IL-12 treatment rescued this phenotype, leading to control of lung tumors. These data suggest that cytokine therapy might be able to rescue a specific subset of dysfunctional T cells found in lung tumors. 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.