Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

Abstract

Although cancer immunotherapy with PD-(L)1 blockade is now routine treatment for patients with lung cancer, remarkably little is known about acquired resistance. We examined 1,201 patients with NSCLC treated with PD-(L)1 blockade to clinically characterize acquired resistance, finding it to be common (occurring in more than 60% of initial responders), with persistent but diminishing risk over time, and with distinct metastatic and survival patterns compared to primary resistance. To examine the molecular phenotype and potential mechanisms of acquired resistance, we performed whole transcriptome and exome tumor profiling in a subset of NSCLC patients (n=29) with acquired resistance. Systematic immunogenomic analysis revealed that tumors with acquired resistance generally had enriched signals of inflammation (including IFNγ signaling and inferred CD8+ T cells) and could be separated into IFNγ upregulated and stable subsets. IFNγ upregulated tumors had putative routes of resistance with signatures of dysfunctional interferon signaling and mutations in antigen presentation genes. Transcriptomic profiling of cancer cells from a murine model of acquired resistance to PD-(L)1 blockade also showed evidence of dysfunctional interferon signaling and acquired insensitivity to in vitro interferon gamma treatment. In summary, we characterized clinical and molecular features of acquired resistance to PD-(L)1 blockade in NSCLC and found evidence of ongoing but dysfunctional IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance.

Durable Response and Improved CD8 T Cell Plasticity in Lung Cancer Patients After PD1 Blockade and JAK Inhibition

“…Conversely, recent evidence suggests that cancer cells may co-opt IFN-I signaling to drive plasticity rather than differentiation 31 . Genome-wide genetic screens in several mouse cancer models have additionally confirmed how IFN signaling in cancer cells can promote ICB resistance 32 , consistent with elevated levels of ISGs in tumors from patients with NSCLC who have relapsed after anti-PD1 2 . Thus, JAK inhibition may improve ICB not only by antagonizing IFN-I signaling in CD8 T cells but also by inhibiting an IFN-driven resistant state in cancer cells.…”

“…In cancer, which represents another disease characterized by chronic inflammation, persistent IFN signaling in cancer cells renders tumors resistant to ICB 8 . Indeed, high levels of a subset of ISGs in cancer cells is associated with immunotherapy resistance in multiple human tumors, including in NSCLC after acquired resistance to anti-PD1 blockade 2 . In CD8 T cells from patients with NSCLC and other types of cancer, high levels of ISGs are coupled to differentiation toward terminal states that include T cell exhaustion 9 .…”

“…In this select group, this response rate is greater than with chemotherapy alone, making immunotherapy the current standard of care for first-line therapy of patients with metastatic NSCLC that is PDL1 ≥ 50%. Despite this improvement, approximately two-thirds of patients with NSCLC who respond to pembrolizumab will relapse 2 , making development of approaches that can improve response rates and/or augment the durability of responses an important goal in immune checkpoint blockade (ICB) therapy.…”