Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells

Abstract

The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes.

Resistance to immune checkpoint inhibitors in KRAS-mutant non-small cell lung cancer

“…Studies have also asserted that excess metabolites, such as lactate, alter the environment and affect the functions of immune cells [60,86,87,89,121] . A more comprehensive description of cancer metabolic reprogramming and immune response can be found in other reviews [122][123][124][125] . Collectively, the limited nutrients and redundant metabolites arouse the dysfunction in immune cells, which is one of the leading causes of resistance to ICIs.…”

“…Therefore, targeting pathways modulating PD-1/-L1 expression might show potential for overcoming the resistance to ICIs, which has been demonstrated in several studies. In the KRAS-mutant lung cancer model, blockade of both PD-1 and helix-loop-helix transcription factor inhibitor of differentiation 1 knock out significantly enhances the amount of CD8 + T cells as well as the expression of PD-L1, which impairs the tumor growth and increases the survival [ 126 ] . In other studies of KRAS mut lung cancer, anti-PD-1 combined with inhibition of the AKT-mTOR pathway by mTOR inhibitor or the STAT3 pathway by natural compound luteolin can remarkably decreased the expression of PD-1 or PD-L1, respectively, which consequently surmounts the resistance to anti-PD-1 [ 127 , 128 ] .…”

Integrating single-cell and bulk RNA sequencing to develop a cancer-associated fibroblast-related signature for immune infiltration prediction and prognosis in lung adenocarcinoma

“…In addition, it exerts antitumor immunosuppressive effects by inhibiting dendritic cell differentiation and CD8 + T cell proliferation ( 53 , 54 ). Baraibar et al showed that programmed cell death protein 1 (PD-1) blockade combined with ID1 inhibition increased the infiltration of CD8 + T cells and their programmed death-ligand 1 (PD-L1) expression, thereby significantly enhancing the immunotherapeutic effect ( 55 ). This result explains the lower CD8 + T lymphocyte infiltration in the high-risk group.…”

Efficacy of immune checkpoint inhibitors in SMARCA4-deficient and TP53 mutant undifferentiated lung cancer

“…Although it has been reported that TP53 or KRAS mutant NSCLC patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to anti-PD-1 inhibitors by some literatures, [11–13] patients with co-occurring SMARCA4/KRAS mutations were presented with extremely poor prognosis. In that retrospective research, the deleterious effect on immunotherapy outcomes in SMARCA4-deficient/KRAS-mutant NSCLC was showed as a lower ORR (22% vs 0%, P = .03), a significantly shorter mPFS (4.1 vs 1.4 months, HR = 0.25 [95% CI: 0.14–0.42], P < .001), and a significantly shorter median overall survival (15.1 vs 3.0 months, HR = 0.29 [95% CI: 0.17–0.50], P < .001) compared with SMARCA4-wt KRAS-mutant NSCLCs.…”