Interrelations between Patients’ Clinicopathological Characteristics and Their Association with Response to Immunotherapy in a Real-World Cohort of NSCLC Patients

Callejo, Ana; Frigola, Joan; Iranzo, Patricia Izquierdo; Carbonell, Caterina; Díaz, N Carames; Marmolejo, David; Assaf, J.D.; Cedrés, S.; Martinez-Martí, Alex; Navarro, Alejandro; Pardo, Núria; Amat, Ramon; Felip, Enriqueta

doi:10.3390/cancers13133249

Cited by 10 publications

(8 citation statements)

References 31 publications

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“… 33 In a recent study analyzing clinicopathological features, female sex—among other characteristics—was associated with increased PFS following ICIs treatment in NSCLC. 34 …”

Section: Discussionmentioning

confidence: 99%

High levels of chromosomal aberrations negatively associate with benefit to checkpoint inhibition in NSCLC

Frigola

Carbonell

Irazno

et al. 2022

J Immunother Cancer

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BackgroundImmune checkpoint inhibitors (ICIs) targeting the programmed cell death 1/programmed death-ligand 1 axis have transformed the management of advanced non-small cell lung cancer (NSCLC). However, many patients do not benefit from this type of treatment, and thus several molecular biomarkers of benefit have been explored. The value of somatic copy number alterations (SCNAs) burden remains elusive.Patients and methodsWe assembled a cohort of 109 patients with NSCLC treated with ICIs and available tumor samples. We performed shallow whole-genome sequencing on 89 patients to determine genome-wide SCNAs and targeted gene expression analysis on 63 patients to study immune infiltration. We analyzed SCNAs burden in different ways (ie, the fraction of the genome altered or number of events) and studied their association with ICIs benefit based on survival analysis. We correlated SCNAs burden and immune infiltration on 35 patients of our cohort and on patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA).ResultsHigh SCNAs burden, computed in diverse ways, is negatively associated with ICIs progression-free survival (PFS), with the fraction of the genome altered (FGA) by arm and chromosome events showing the strongest association with PFS (p=0.002) (n=77). Nevertheless, we found differences in SCNAs across some clinicopathological features (sample site origin). A multivariate analysis adjusted for relevant characteristics showed that the FGA of arm and chromosome alterations was strongly associated with PFS (HR=2.21, p=3.3 x 10−5). Finally, we confirmed that SCNAs burden negatively correlates with tumor immune infiltration (n=35), although this correlation was not found for the males studied. Similar results were observed in the TCGA cohort.ConclusionsSCNAs burden is a potential biomarker of benefit to ICIs in patients with NSCLC, although there appear to be some nuances worth consideration. Further studies will be needed to establish its role as a biomarker of benefit to ICIs.

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“… 33 In a recent study analyzing clinicopathological features, female sex—among other characteristics—was associated with increased PFS following ICIs treatment in NSCLC. 34 …”

Section: Discussionmentioning

confidence: 99%

High levels of chromosomal aberrations negatively associate with benefit to checkpoint inhibition in NSCLC

Frigola

Carbonell

Irazno

et al. 2022

J Immunother Cancer

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“…Based on our in-house cohort, we found that the use of statin was remarkably related to improved clinical outcome in NSCLC patients. Although multiple studies have uncovered the combination of statin with PD-1 inhibitors in various cancers (44)(45)(46)(47)(48)(49), these clinical studies had too few patients receiving statin to evaluate potential confounding effects. Therefore, we conducted a meta-analysis to assess the effect of statin use on anti-PD-1 immunotherapy, and we observed a potential indication that the use of statin may improve OS in the NSCLC patients receiving immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Statin shapes inflamed tumor microenvironment and enhances immune checkpoint blockade in non–small cell lung cancer

Mao¹,

Cai²,

Chen³

et al. 2022

JCI Insight

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Immune checkpoint blockade (ICB) therapy has achieved breakthroughs in the treatment of advanced non-small cell lung cancer (NSCLC). Nevertheless, the low response due to immuno-cold tumor microenvironment (TME) largely limits the application of ICB therapy. Based on the glycolytic/cholesterol synthesis axis, a stratification framework for EGFR wild-type NSCLC was developed to summarize the metabolic features of immuno-cold and immuno-hot tumors. The cholesterol subgroup displays the worst prognosis in immuno-cold NSCLC with significant enrichment of the cholesterol gene signature, indicating targeting cholesterol synthesis is essential for the therapy for immuno-cold NSCLC. Statin, the inhibitor for cholesterol synthesis, can suppress the aggressiveness of NSCLC in vitro and in vivo and also drastically reverse immuno-cold to an inflamed phenotype in vivo which exhibited a higher response to ICB therapy. Moreover, both our in-house data and meta-analysis further support that statin can significantly enhance ICB efficacy. In terms of preliminary mechanisms, statin could transcriptionally inhibit PD-L1 expression and induce ferroptosis in NSCLC cells. Overall, we reveal the significance of cholesterol synthesis in NSCLC and demonstrate the improved therapeutic efficacy of ICB in combination with statin.These findings could provide a innovative clinical insight to treat NSCLC patients with immuno-cold tumors.

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“… Other clinical factors: The best association for any response to immunotherapy was found with the combination of LDH levels, TRAEs, and sex. Thus several clinicopathological features may be utilized as biomarkers in the real world 155. Several other relevant clinical factors, including poor performance status due to cancer-related conditions, metastasis, concomitant therapies, and radiologic features have been related to a reduced clinical benefit from ICI 156–158…”

Section: Biomarkersmentioning

confidence: 99%

Role of Surgical Pathologist for the Detection of Immuno-oncologic Predictive Factors in Non-small Cell Lung Cancers

Mohanty¹,

Mishra

Amin

et al. 2023

Advances in Anatomic Pathology

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Until very recently, surgery, chemotherapy, and radiation therapy have been the mainstay of treatment in non-small cell carcinomas (NSCLCs). However, recent advances in molecular immunology have unveiled some of the complexity of the mechanisms regulating cellular immune responses and led to the successful targeting of immune checkpoints in attempts to enhance antitumor T-cell responses. Immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4, programmed cell death protein-1, and programmed death ligand (PD-L) 1 have been shown to play central roles in evading cancer immunity. Thus, these molecules have been targeted by inhibitors for the management of cancers forming the basis of immunotherapy. Advanced NSCLC has been the paradigm for the benefits of immunotherapy in any cancer. Treatment decisions are made based on the expression of PD-L1 on the tumor cells and the presence or absence of driver mutations. Patients with high PD-L1 expression (≥50%) and no driver mutations are treated with single-agent immunotherapy whereas, for all other patients with a lower level of PD-L1 expression, a combination of chemotherapy and immunotherapy is preferred. Thus, PD-L1 blockers are the only immunotherapeutic agents approved in advanced NSCLC without any oncogenic driver mutations. PD-L1 immunohistochemistry, however, may not be the best biomarker in view of its dynamic nature in time and space, and the benefits may be seen regardless of PD -L1 expression. Each immunotherapy molecule is prescribed based on the levels of PD-L1 expression as assessed by a Food and Drug Administration-approved companion diagnostic assay. Other biomarkers that have been studied include tumor mutational burden, the T-effector signature, tumor-infiltrating lymphocytes, radiomic assays, inflammation index, presence or absence of immune-related adverse events and specific driver mutations, and gut as well as local microbiome. At the current time, none of these biomarkers are routinely used in the clinical decision-making process for immunotherapy in NSCLC. However, in individual cases, they can be useful adjuncts to conventional therapy. This review describes our current understanding of the role of biomarkers as predictors of response to immune checkpoint molecules. To begin with a brief on cancer immunology in general and in NSCLC, in particular, is discussed. In the end, recent advancements in laboratory techniques for refining biomarker assays are described.

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Interrelations between Patients’ Clinicopathological Characteristics and Their Association with Response to Immunotherapy in a Real-World Cohort of NSCLC Patients

Cited by 10 publications

References 31 publications

High levels of chromosomal aberrations negatively associate with benefit to checkpoint inhibition in NSCLC

High levels of chromosomal aberrations negatively associate with benefit to checkpoint inhibition in NSCLC

Statin shapes inflamed tumor microenvironment and enhances immune checkpoint blockade in non–small cell lung cancer

Role of Surgical Pathologist for the Detection of Immuno-oncologic Predictive Factors in Non-small Cell Lung Cancers

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