bims-meluca 2023-12-10 papers

Clin Cancer Res. 2023 Dec 01.

TROP2 is associated with primary resistance to immune checkpoint inhibition in patients with advanced non-small cell lung cancer.

Alban Bessede, Florent Peyraud, Benjamin Besse, Sophie Cousin, Mathilde Cabart, François Chomy, Christophe Rey, Oren Lara, Ophélie Odin, Imane Nafia, Lucile Vanhersecke, Fabrice Barlesi, Jean-Philippe Guégan, Antoine Italiano.

PURPOSE: Mechanisms of primary resistance to inhibitors of the programmed cell death-1 (PD-1/PD-L1) signaling axis in non-small cell lung cancer (NSCLC) are still poorly understood. While some studies suggest TROP2's involvement in modulating tumor cell resistance to therapeutic drugs, its specific role in the context of PD1/PD-L1 axis blockade is not definitively established.
EXPERIMENTAL DESIGN: We performed high-throughput analysis of transcriptomic data from 891 NSCLC tumors from patients treated with either the PD-L1 inhibitor atezolizumab or chemotherapy in two large randomized clinical trials. To confirm our results at the protein level, we complemented this transcriptional approach by performing a multiplex immunofluorescence analysis of tumor tissue samples as well as a proteomic profiling of plasma.
RESULTS: We observed a significant association of TROP2 overexpression with worse progression-free survival and overall survival on PD-L1 blockade, independent of other prognostic factors. Importantly, we found increased TROP2 expression to be predictive of survival in patients treated with atezolizumab, but not chemotherapy. TROP2 overexpression was associated with decreased T cell infiltration. We confirmed these results at the proteomic level both on tumor tissue and in plasma.
CONCLUSION: Our results suggest an important contribution of TROP2 expression to the primary resistance to PD-L1 blockade in NSCLC. TROP2-biomarker-based strategy may be relevant in selecting NSCLC patients who are more likely to benefit from a combination of immunotherapy and an anti-TROP2 agent.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-2566

Am J Cancer Res. 2023 ;13(11): 5443-5454

Characteristics of the immune microenvironment associated with RRM2 expression and its application to PD-L1/PD-1 inhibitors in lung adenocarcinoma.

Seul-Ki Lee, Yoonjung Hwang, Jae-Ho Han, Seokjin Haam, Hyun Woo Lee, Young Wha Koh.

Recent studies have indicated that RRM2 plays a crucial part in the tumor immune microenvironment. According to the expression of RRM2, we evaluated immune cell infiltration, immunotherapy biomarkers, and the expression of immune checkpoint molecules in four lung adenocarcinoma (LUAD) datasets. We employed the Tumor Immune Dysfunction and Exclusion (TIDE) and CIBERSORTx algorithms to examine the patterns of immune cell distribution and evaluate the responses to anti-programmed death protein-1/programmed death ligand-1 (PD-1/PD-L1) therapy in three publicly available LUAD datasets. These findings were corroborated using a validation group comprising patients who received treatment with PD-1/PD-L1 inhibitors. Additionally, we conducted experiments using LUAD cell lines to investigate how RRM2 affects the expression of PD-L1. In comparison to the low RRM2 group, the high RRM2 group exhibited a high interferon gamma signature, high T-cell-inflamed signature, high CD274 expression, high CD8+ T cell levels, low cancer-associated fibroblasts, and low M2 macrophages, according to TIDE analysis in the three LUAD datasets. Analysis of the three LUAD datasets using CIBERSORTx confirmed a positive correlation between RRM2 and CD8+ T cells, and this finding was validated by immunohistochemistry in a separate validation set. In the three LUAD datasets without PD-1/PD-L1 inhibitor treatment, higher RRM2 expression was associated with a poorer prognosis. However, in the LUAD dataset treated with PD-1/PD-L1 inhibitors, higher RRM2 expression was associated with better prognosis. In the three datasets, the high-RRM2 group exhibited higher expression of inhibitory immune checkpoint molecules. In a LUAD cell line study, we discovered that RRM2 regulates PD-L1 expression through the ANXA1/AKT pathway. The expression of RRM2 shows promise as a predictive biomarker for PD-1/PD-L1 inhibitors in LUAD patients, and it may represent a new target to overcome resistance to PD-L1/PD-1 therapies.

Keywords: CD8; Lung adenocarcinoma; PD-1; PD-L1; RRM2; macrophage

Cell Rep Med. 2023 Nov 28. pii: S2666-3791(23)00496-2. [Epub ahead of print] 101302

Tumor-immune microenvironment and NRF2 associate with clinical efficacy of PD-1 blockade combined with chemotherapy in lung squamous cell carcinoma.

The RATIONALE-307 study (ClinicalTrials.gov: NCT03594747) demonstrates prolonged progression-free survival (PFS) with first-line tislelizumab plus chemotherapy versus chemotherapy in advanced lung squamous cell carcinoma (LUSC; N = 360). Here we describe an immune-related gene expression signature (GES), composed of genes involved in both innate and adaptive immunity, that appears to differentiate tislelizumab plus chemotherapy PFS benefit versus chemotherapy. In contrast, a tislelizumab plus chemotherapy PFS benefit is observed regardless of programmed death ligand 1 (PD-L1) expression or tumor mutational burden (TMB). Genetic analysis reveals that NRF2 pathway activation is enriched in PD-L1positive and TMBhigh patients. NRF2 pathway activation is negatively associated with PFS, which affects efficacy outcomes associated with PD-L1 and TMB status, impairing their predictive potential. Mechanistic studies demonstrate that NRF2 directly mediates PD-L1 constitutive expression independent of adaptive PD-L1 regulation in LUSC. In summary, the GES is an immune signature that might identify LUSC patients likely to benefit from first-line tislelizumab plus chemotherapy.

Keywords: NRF2; PD-1 blockade; PD-L1; biomarkers; clinical trial; gene expression signature; immunotheraphy; squamous NSCLC; tislelizumab; tumor mutational burden

DOI: https://doi.org/10.1016/j.xcrm.2023.101302