Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival

Abstract

Success of immune checkpoint inhibitors in advanced non-small-cell lung cancer (NSCLC) has invigorated their use in the neoadjuvant setting for early-stage disease. However, the cellular and molecular mechanisms of the early immune responses to therapy remain poorly understood. Through an integrated analysis of early-stage NSCLC patients and a Kras mutant mouse model, we show a prevalent programmed cell death 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis exemplified by increased intratumoral PD-1+ T cells and PD-L1 expression. Notably, tumor progression was associated with spatiotemporal modulation of the immune microenvironment with dominant immunosuppressive phenotypes at later phases of tumor growth. Importantly, PD-1 inhibition controlled tumor growth, improved overall survival, and reprogrammed tumor-associated lymphoid and myeloid cells. Depletion of T lymphocyte subsets demonstrated synergistic effects of those populations on PD-1 inhibition of tumor growth. Transcriptome analyses revealed T cell subset-specific alterations corresponding to degree of response to the treatment. These results provide insights into temporal evolution of the phenotypic effects of PD-1/PD-L1 activation and inhibition and motivate targeting of this axis early in lung cancer progression.

Functional systemic CD 4 immunity is required for clinical responses to PD ‐L1/ PD ‐1 blockade therapy

“…The requirement of functional systemic immunity has been previously demonstrated in murine models for the efficacy of other immunotherapy approaches (Spitzer et al , ), as well as the importance of CD4 T cells for anti‐PD‐1 immunotherapy (Markowitz et al , ). These studies are in agreement with our present data in human patients undergoing PD‐L1/PD‐1 blockade therapies.…”

Deciphering the transcriptomic landscape of tumor-infiltrating CD8 lymphocytes in B16 melanoma tumors with single-cell RNA-Seq

“…Next, we performed gene-set enrichment analysis (GSEA) on published bulk RNA-seq data of CD8 TILs following anti-PD-1 therapy (raw data in murine sarcoma from (Gubin et al, 2014). Our results indicated that ICB led to a selective enrichment of the EM-like signature (p=0.035, Figure 6 A, raw data from (Markowitz et al, 2018)).…”

“…RNA-seq data of CD8 TILs in murine sarcoma (tumors were harvested at day 12 post-transplant, 3 days after treatment) was obtained from GEO accession GSE62771 (anti-PD-1 vs control) (Gubin et al, 2014). RNA-seq data of CD8 TILs in non-small cell lung cancer (anti-PD1 vs control) were obtained from GEO accession GSE114300 (Markowitz et al, 2018). RNA-seq data from adoptively transferred (in vitro activated) OT-1 cells infiltrating B16-OVA tumors (anti-PD1 vs control) were obtained from GEO GSE93014 (Mognol et al, 2017).…”

Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment

“…In the past decade, and while exploration of the immune landscape of PMLs was still in its infancy, immunotherapy was tested in early stage lung tumors with promising results (245,246). Interestingly, early-stage LUADs treated with standard adjuvant therapy exhibited mutations in genes involved in immune regulation that are also associated with smoking (211).…”