Emerging biomarkers for neoadjuvant immune checkpoint inhibitors in operable non-small cell lung cancer

Pradhan, Monika; Chocry, Mathieu; Gibbons, Don L.; Sepesi, Boris; Cascone, Tina

doi:10.21037/tlcr-20-573

Cited by 29 publications

(43 citation statements)

References 108 publications

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“…Because of its relevance in triggering cancer-related tolerance in NSCLC and for its targetability in immunotherapy with immune-checkpoint inhibitors, which NSCLC is particularly responsive to [ 37 ], we chose to also investigate the immunohistochemical expression of the immune-checkpoint molecule PD-L1. The absence of statistically significant associations between a high or low Kyn/Trp ratio, and high or low immunohistochemical expression of PD-L1, in the whole NSCLC population, or within the two histotype subgroups, suggests that these two markers should be carefully considered in the stratification of patients to be treated with an immunotherapy combining the inhibition of IDO1 and the blockade of programmed cell death-1 (PD-1)/PD-L1 interaction.…”

Section: Discussionmentioning

confidence: 99%

“…The absence of statistically significant associations between a high or low Kyn/Trp ratio, and high or low immunohistochemical expression of PD-L1, in the whole NSCLC population, or within the two histotype subgroups, suggests that these two markers should be carefully considered in the stratification of patients to be treated with an immunotherapy combining the inhibition of IDO1 and the blockade of programmed cell death-1 (PD-1)/PD-L1 interaction. Such dual-agent therapy has been proposed for NSCLC [ 38 , 39 ] and is currently evaluated by oncological clinical trials [ 40 ] to maximize the clinical benefit of immune-checkpoint inhibitors, not effective on a significant fraction of NSCLC patients [ 37 ]. In evaluating the criteria for stratification of patients, not only the immunohistochemical expression of PD-L1 in tumor cells should be considered, but also the circulating component of soluble PD-L1, contributing to PD-1 receptor activation and, consequently, to the onset of cancer-permissive tolerance [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

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Kynurenine/Tryptophan Ratio as a Potential Blood-Based Biomarker in Non-Small Cell Lung Cancer

Mandarano

Orecchini

Bellezza

et al. 2021

IJMS

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The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrade tryptophan (Trp) into kynurenine (Kyn) at the initial step of an enzymatic pathway affecting T cell proliferation. IDO1 is highly expressed in various cancer types and associated with poor prognosis. Nevertheless, the serum Kyn/Trp concentration ratio has been suggested as a marker of cancer-associated immune suppression. We measured Kyn and Trp in blood samples of a wide cohort of non-small-cell lung cancer (NSCLC) patients, before they underwent surgery, and analyzed possible correlations of the Kyn/Trp ratio with either IDO1 expression or clinical–pathological parameters. Low Kyn/Trp significantly correlated with low IDO1 expression and never-smoker patients; while high Kyn/Trp was significantly associated with older (≥68 years) patients, advanced tumor stage, and squamous cell carcinoma (Sqcc), rather than the adenocarcinoma (Adc) histotype. Moreover, high Kyn/Trp was associated, among the Adc group, with higher tumor stages (II and III), and, among the Sqcc group, with a high density of tumor-infiltrating lymphocytes. A trend correlating the high Kyn/Trp ratio with the probability of recurrences from NSCLC was also found. In conclusion, high serum Kyn/Trp ratio, associated with clinical and histopathological parameters, may serve as a serum biomarker to optimize risk stratification and therapy of NSCLC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Kynurenine/Tryptophan Ratio as a Potential Blood-Based Biomarker in Non-Small Cell Lung Cancer

Mandarano

Orecchini

Bellezza

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…As PD-L1 is expressed on the surface of tumour cells to inhibit T cells and survive their cytotoxic activities, degree of immunohistochemical measurement of PD-L1 in biopsy materials is being investigated as a biomarker of responses to ICIs (3). However, the role of PD-L1 is still under debate due to the disparities between previous studies (3,(7)(8)(9).…”

Section: Pd-l1 Expressionmentioning

confidence: 99%

“…Non-small cell lung cancer (NSCLC) is the most frequent subtype of lung cancer which is one of the most lethal cancers worldwide. Although its incidence rates and ageadjusted death rates have been falling each year, the 5-year relative survival is still low even in patients with resectable disease due to local or distant recurrences after surgery (ranging from 25% to 70%) (1)(2)(3). Neoadjuvant and adjuvant treatment strategies such as chemotherapy, targeted therapy and immunotherapy have therefore received much attention in the last years to reduce the risk of postoperative recurrence of resectable NSCLC and provide an improvement in survival rates (2).…”

Section: Introductionmentioning

confidence: 99%

Biomarkers under investigation for neoadjuvant immune checkpoint inhibitors in non-small cell lung cancer

Söyler¹,

Yılmaz²

2022

AME Surg J

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The 5-year relative survival of non-small cell lung cancer (NSCLC) is still low even in patients with resectable disease due to local or distant recurrences after surgery. Novel treatment strategies are essential to reduce the risk of postoperative recurrence and provide an improvement in survival rates.Although neoadjuvant immune checkpoint inhibitors (ICIs) are not included in the treatment protocols yet, investigations are still ongoing. However, one of the major issues encountered in this regard is the ideal patient selection. Furthermore, ICIs have several limitations such as serious side effects, high costs and varying response rates among patients. Thus, the development of accurate biomarkers is necessary for ideal patient selection, risk stratification and prediction of treatment response in patients. Biomarkers under investigation for neoadjuvant ICIs in NSCLC are being evaluated in four major categories: tumour cellassociated biomarkers, tumour microenvironment-related biomarkers, liquid biopsy-related biomarkers and host-related markers. In addition, 18 F-FDG PET-CT parameters may be used in this regard. Emerging results from clinical trials suggest that these biomarkers may play important roles in the management of NSCLC in the near future. Nevertheless, there are still many unknowns about mechanisms of biomarkers. Some challenges, such as clinical adaptability, validation and feasibility, also exist. It should be noted that, there are no currently standardized biomarkers to select the ideal patient. Further studies are therefore required to identify reliable biomarkers in the prediction of response and outcome of ICIs.

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“…Despite the promising results, biomarkers that predict the pathological responses to immunotherapy alone or chemo-immunotherapy are still lacking (9,(34)(35)(36). This is a critical issue because the subsequent invasive surgery can be obviated in patients who have a pathological CR after ICI therapy.…”

Section: Biomarkers Predicting Responses To Immunotherapymentioning

confidence: 99%

Smoking signature is superior to programmed death-ligand 1 expression in predicting pathological response to neoadjuvant immunotherapy in lung cancer patients

Yang¹,

Ma²,

Sun³

et al. 2021

Transl Lung Cancer Res

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Background: There is a paucity of biomarkers that can predict the degree of pathological response [e.g., pathological complete response (pCR) or major response (pMR)] to immunotherapy. Neoadjuvant immunotherapy provides an ideal setting for exploring responsive biomarkers because the pathological responses can be directly and accurately evaluated.Methods: We retrospectively collected the clinicopathological characteristics and treatment outcomes of non-small cell lung cancer (NSCLC) patients who received neoadjuvant immunotherapy or chemoimmunotherapy followed by surgery between 2018 and 2020 at a large academic thoracic cancer center.Clinicopathological factors associated with pathological response were analyzed.Results: A total of 39 patients (35 males and 4 females) were included. The most common histological subtype was lung squamous cell carcinoma (LUSC) (n=28, 71.8%), followed by lung adenocarcinoma (LUAD) (n=11, 28.2%). After neoadjuvant treatment, computed tomography (CT) scan-based evaluation showed poor agreement with the postoperatively pathological examination (weighted kappa =0.0225; P=0.795), suggesting the poor performance of CT scans in evaluating the response to immunotherapy. Importantly, we found that the smoking signature displayed a better performance than programmed death-ligand 1 (PD-L1) expression in predicting the pathological response (area under the curve: 0.690 vs. 0.456; P=0.0259), which might have resulted from increased tumor mutational burden (TMB) and/or microsatellite instability (MSI) relating to smoking exposure.Conclusions: These findings suggest that CT scan-based evaluation is not able to accurately reflect the pathological response to immunotherapy and that smoking signature is a superior marker to PD-L1 expression in predicting the benefit of immunotherapy in NSCLC patients.

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Emerging biomarkers for neoadjuvant immune checkpoint inhibitors in operable non-small cell lung cancer

Cited by 29 publications

References 108 publications

Kynurenine/Tryptophan Ratio as a Potential Blood-Based Biomarker in Non-Small Cell Lung Cancer

Kynurenine/Tryptophan Ratio as a Potential Blood-Based Biomarker in Non-Small Cell Lung Cancer

Biomarkers under investigation for neoadjuvant immune checkpoint inhibitors in non-small cell lung cancer

Smoking signature is superior to programmed death-ligand 1 expression in predicting pathological response to neoadjuvant immunotherapy in lung cancer patients

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