Predictive Capability of PD-L1 Protein Expression for Patients With Advanced NSCLC: Any Differences Based on Histology?

Meshulami, Noy; Tavolacci, Sooyun; Miguel-Perez, Diego de; Rolfo, Christian; Mack, Philip C.; Hirsch, Fred R.

doi:10.1016/j.cllc.2023.03.014

Cited by 8 publications

(7 citation statements)

References 41 publications

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“…Historically, the prevailing consensus in research predominantly favored LUSC for ICB therapy because of its higher PD‐L1 positivity and tumor mutation burden. However, recent studies have reported a noteworthy shift in perspective: PD‐L1 demonstrates superior predictive value for immunotherapy response in LUAD, with LUAD patients exhibiting enhanced survival during anti‐PD‐1/PD‐L1 drug treatment 93 . In the present study, we harnessed data from previously published single‐cell datasets to collectively characterize the tumor microenvironment of NSCLC, with relevant results complemented by bulk data and validated by mIF.…”

Section: Discussionmentioning

confidence: 99%

Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single‐cell transcriptomic analysis: Implications for distinct immunotherapy outcomes

Fang,

Li,

Wan

et al. 2024

The Journal of Gene Medicine

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BackgroundImmune checkpoint blockade has emerged as a key strategy to the therapy landscape of non‐small cell lung cancer (NSCLC). However, notable differences in immunotherapeutic outcomes exist between the two primary NSCLC subtypes: lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). This disparity may stem from the tumor immune microenvironment's heterogeneity at the transcriptome level.MethodsBy integrative analysis of transcriptomic characterization of 38 NSCLC patients by single‐cell RNA sequencing, the present study revealed a distinct tumor microenvironment (TME) between LUAD and LUSC, with relevant results further confirmed in bulk transcriptomic and multiplex immunofluorescence (mIF) validation cohort of neoadjuvant immunotherapy patients.ResultsLUAD exhibited a more active immune microenvironment compared to LUSC. This included highly expression of HLA I/II in cancer cells, reinforced antigen presentation potential of dendritic cells and enhanced cytotoxic activity observed in T/NK cells. In LUSC, cancer cells highly expressed genes belonging to the aldo‐keto reductases, glutathione S‐transferases and aldehyde dehydrogenase family, negatively correlating with immunotherapy outcomes in the validation cohort of our center. Further analysis revealed elevated infiltrated cancer‐associated fibroblasts (CAFs) in LUSC, which was corroborated in The Cancer Genome Atlas cohort. Corresponding increased infiltration of ADH1B+ CAFs in major pathologic response (MPR) patients and the higher presence of FAP+ CAFs in non‐MPR patients were demonstrated by multiplex mIF. Moreover, upregulating immunosuppressive extracellular matrix remodeling was identified in LUSC.ConclusionsThese comprehensive analyses advance the understanding of the differences in TME between LUAD and LUSC, offering insights for patient selection and developing subtype‐specific treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single‐cell transcriptomic analysis: Implications for distinct immunotherapy outcomes

Fang,

Li,

Wan

et al. 2024

The Journal of Gene Medicine

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“…Furthermore, some drugs are tailored to the staining of tumor cells, while others also consider the PD-L1 status of immune cells. The predictive value of PD-L1 may be distinct even for seemingly similar drugs, e.g., pembrolizumab and nivolumab, and these differences are observed even for patients with the same tumor type [130][131][132][133][134]. Importantly, there is no any biological or medical rationale explaining these controversies.…”

Section: Pd-l1mentioning

confidence: 99%

“…For example, there are many nuances regarding the use of PD-L1 status for the selection of treatment strategy in lung cancer. In fact, PD-L1 determination plays a critical role mainly in the choice of first-line therapy, because tumors with high expression (≥50% tumor cells) can be treated by ICIs without the addition of chemotherapy [131][132][133]. Combined administration of ICIs and cytotoxic drugs, as well as the use of ICIs in pretreated patients, generally do not require determination of PD-L1 status.…”

Section: Pd-l1mentioning

confidence: 99%

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

Aleksakhina,

Ivantsov,

Imyanitov

2024

IJMS

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Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying ALK and ROS1 translocations, biallelic BRCA1/2 inactivation and/or homologous recombination deficiency (HRD), strong HER2 amplification/overexpression coupled with the absence of other MAPK pathway-activating mutations, etc. On the other hand, some well-known targets are not agnostic: for example, PD-L1 expression is predictive for the efficacy of PD-L1/PD1 inhibitors only in some but not all cancer types. Unfortunately, the individual probability of finding a druggable target in a given tumor is relatively low, even with the use of comprehensive next-generation sequencing (NGS) assays. Nevertheless, the rapidly growing utilization of NGS will significantly increase the number of patients with highly unusual or exceptionally rare tumor-target combinations. Clinical trials may provide only a framework for treatment attitudes, while the decisions for individual patients usually require case-by-case consideration of the probability of deriving benefit from agnostic versus standard therapy, drug availability, associated costs, and other circumstances. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.

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“…Non-small cell lung cancers (NSCLCs) represent 85 % of lung tumors [ 1 ]. The KRAS p. G12C mutation occurs in 13 % of NSCLCs and in 1–3 % of colorectal cancers and other cancers [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Post-marketing safety concerns of sotorasib: A disproportionality analysis based on FDA adverse event reporting system

Ding,

Su,

Shu

et al. 2024

Heliyon

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Predictive Capability of PD-L1 Protein Expression for Patients With Advanced NSCLC: Any Differences Based on Histology?

Cited by 8 publications

References 41 publications

Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single‐cell transcriptomic analysis: Implications for distinct immunotherapy outcomes

Insights into the heterogeneity of the tumor microenvironment in lung adenocarcinoma and squamous carcinoma through single‐cell transcriptomic analysis: Implications for distinct immunotherapy outcomes

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

Post-marketing safety concerns of sotorasib: A disproportionality analysis based on FDA adverse event reporting system

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