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Composite biomarkers defined by multiparametric immunofluorescence analysis identify ALK-positive adenocarcinoma as a potential target for immunotherapy.

ABSTRACT: Anaplastic lymphoma kinase (ALK) inhibitors have been successfully developed for non-small cell lung carcinoma (NSCLC) displaying chromosomal rearrangements of the ALK gene, but unfortunately resistance invariably occurs. Blockade of the PD-1-PD-L1/2 inhibitory pathway constitutes a breakthrough for the treatment of NSCLC. Some predictive biomarkers of clinical response to this therapy are starting to emerge, such as PD-L1 expression by tumor/stromal cells and infiltration by CD8⁺ T cells expressing PD-1. To more effectively integrate all of these potential biomarkers of clinical response to immunotherapy, we have developed a multiparametric immunofluorescence technique with automated immune cell counting to comprehensively analyze the tumor microenvironment of ALK-positive adenocarcinoma (ADC). When analyzed as either a continuous or a dichotomous variable, the mean number of tumor cells expressing PD-L1 (p = 0.012) and the percentage of tumor cells expressing PD-L1 were higher in ALK-positive ADC than in EGFR-mutated ADC or WT (non-EGFR-mutated and non-KRAS-mutated) NSCLC. A very strong correlation between PD-L1 expression on tumor cells and intratumoral infiltration by CD8⁺ T cells was observed, suggesting that an adaptive mechanism may partly regulate this expression. A higher frequency of tumors combining positive PD-L1 expression and infiltration by intratumoral CD8⁺ T cells or PD-1⁺CD8⁺ T cells was also observed in ALK-positive lung cancer patients compared with EGFR-mutated (p = 0.03) or WT patients (p = 0.012). These results strongly suggest that a subgroup of ALK-positive lung cancer patients may constitute good candidates for anti-PD-1/-PD-L1 therapies.

SUBMITTER: Roussel H

PROVIDER: S-EPMC5414864 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Composite biomarkers defined by multiparametric immunofluorescence analysis identify ALK-positive adenocarcinoma as a potential target for immunotherapy.

Roussel Hélène H De Guillebon Eléonore E Biard Lucie L Mandavit Marion M Gibault Laure L Fabre Elisabeth E Antoine Martine M Hofman Paul P Beau-Faller Michèle M Blons Hélène H Danel Claire C Barthes Françoise Le Pimpec FLP Gey Alain A Granier Clémence C Wislez Marie M Laurent-Puig Pierre P Oudard Stéphane S Bruneval Patrick P Badoual Cécile C Cadranel Jacques J Tartour Eric E

Oncoimmunology 20170221 4

Anaplastic lymphoma kinase (ALK) inhibitors have been successfully developed for non-small cell lung carcinoma (NSCLC) displaying chromosomal rearrangements of the <i>ALK</i> gene, but unfortunately resistance invariably occurs. Blockade of the PD-1-PD-L1/2 inhibitory pathway constitutes a breakthrough for the treatment of NSCLC. Some predictive biomarkers of clinical response to this therapy are starting to emerge, such as PD-L1 expression by tumor/stromal cells and infiltration by CD8<sup>+</s ...[more]

PMID: 28507793

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Project description:IntroductionThe advent of immune checkpoint blockade (ICB) has led to significantly improved disease outcome in lung adenocarcinoma (ADC), but response of ALK/EGFR-positive tumors to immune therapy is limited. The underlying immune biology is incompletely understood.MethodsWe performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles.ResultsWhile total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC = - 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC = - 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine-cytokine receptor signaling, were differentially expressed between the three subgroups. Among the latter, five genes were differently expressed in both ALK-positive and EGFR-positive tumors, while twelve genes showed differential expression solely in ALK-positive tumors and eleven genes solely in EGFR-positive tumors.ConclusionTargeted gene expression profiling is a promising tool to read out tumor microenvironment characteristics from routine diagnostic lung cancer biopsies. Significant immune reactivity including specific immunosuppressive characteristics in ALK- and EGFR-positive lung ADC, but not a total absence of immune infiltration supports further clinical evaluation of immune-modulators as partners of ICB in such tumors.

Project description:IntroductionAnaplastic lymphoma kinase (ALK) fusion mutation is more common in younger and never-smoking lung cancer patients. The association of smoking and ALK-tyrosine kinase inhibitors (TKIs) on overall survival (OS) of treatment-naïve ALK-positive advanced lung adenocarcinoma remains unclear in real-world.MethodsThis retrospective study evaluated all 33170 lung adenocarcinoma patients registered in the National Taiwan Cancer Registry from 2017 to 2019, of whom 9575 advanced stage patients had ALK mutation data.ResultsAmong the 9575 patients, 650 (6.8%) patients had ALK mutation with the median follow-up survival time 30.97 months (median age, 62 years; 125 [19.2%] were aged ≥75 years; 357 (54.9%) females; 179 (27.5) smokers, 461 (70.9%) never-smokers, 10 (1.5%) with unknown smoking status; and 544 (83.7%) with first-line ALK-TKI treatment). Overall, of 535 patients with known smoking status who received first-line ALK-TKI treatment, never-smokers and smokers had a median OS of 40.7 months (95% confidence interval (CI), 33.1-47.2 months) and 23.5 months (95% CI, 11.5-35.5 months) (P=0.015), respectively. Among never-smokers, those who received first-line ALK-TKI treatment had a median OS of 40.7 months (95% CI, 22.7-57.8 months), while those ALK-TKI not as first-line treatment had a median OS of 31.7 months (95% CI, 15.2-42.8 months) (P=0.23). In smokers, the median OS for these patients was 23.5 months (95% CI, 11.5-35.5 months) and 15.6 months (95% CI, 10.2-21.1 months) (P=0.026), respectively.Conclusions and relevanceFor patients with treatment-naïve advanced lung adenocarcinoma, the ALK test should be performed irrespective of smoking status and age. Smokers had shorter median OS than never-smokers among treatment-naïve-ALK-positive patients with first-line ALK-TKI treatment. Furthermore, smokers not receiving first-line ALK-TKI treatment had inferior OS. Further investigations for the first-line treatment of ALK-positive smoking advanced lung adenocarcinoma patients are needed.

Project description:Background Ovarian metastasis is an extremely rare condition in patients with lung adenocarcinoma. Lung adenocarcinoma patients with ovarian metastases were difficult to distinguish from primary ovarian cancer. Anaplastic lymphoma kinase (ALK) gene rearrangement is only found in 3–7% of patients with lung cancer. It is worth noting that the incidence of lung cancer with ovarian metastasis is extremely low, however, ALK rearrangement is often reported in these cases. Here we reported a young woman, aged 23 years, with ALK-positive lung adenocarcinoma and ovarian metastasis. Case Description The patient underwent laparoscopic bilateral ovarian tumor resection after discovering an abdominal mass accidentally. A series of lung adenocarcinoma-specific immunohistochemical features were detected postoperatively by immunohistochemistry (IHC) analysis. Then extensive-stage metastatic masses of different sizes were identified by 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) positron emission tomography combined with low-dose computed tomography (PET/CT), among which the largest nodule was 1.7 cm × 1.4 cm located in the middle lobe of the right lung. Genetic testing of the paraffin tissue DNA revealed the fusion mutation of EML4_ALK (E14:A20) gene. The patient was pathologically diagnosed with lung adenocarcinoma with bilateral ovarian metastasis, administered with oral alectinib [600 mg twice daily (bid)] and followed-up quarterly. Currently, the patient responded to alectinib stably, with a progression-free survival (PFS) of more than 12 months, and experienced no significant adverse events. In addition, we reviewed the publications associated with the characteristics of ALK-positive lung cancer with ovarian metastases and the identification of primary and secondary ovarian tumors. Conclusions This case provides a meaningful reference for the possibility of adnexal metastases from lung cancer, particularly for ALK-rearranged young female patients. In addition, this case highlights the advantages of IHC together with genetic testing for identifying origin sites of ovarian metastases and provides a promising treatment option.

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Composite biomarkers defined by multiparametric immunofluorescence analysis identify ALK-positive adenocarcinoma as a potential target for immunotherapy.

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Composite biomarkers defined by multiparametric immunofluorescence analysis identify ALK-positive adenocarcinoma as a potential target for immunotherapy.

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