Immune related endonucleases and GTPases are not associated with tumor response in patients with advanced non-small cell lung cancer treated with checkpoint inhibitors

H O Ramdani; M Falk; L C Heukamp; S Schatz; M Tiemann; C Wesseler; L Diehl; E Schuuring; H J M Groen; F Griesinger

doi:10.1016/j.prp.2021.153651

Immune related endonucleases and GTPases are not associated with tumor response in patients with advanced non-small cell lung cancer treated with checkpoint inhibitors

Pathol Res Pract. 2021 Nov:227:153651. doi: 10.1016/j.prp.2021.153651. Epub 2021 Oct 12.

Authors

H O Ramdani¹, M Falk², L C Heukamp³, S Schatz⁴, M Tiemann⁵, C Wesseler⁶, L Diehl⁷, E Schuuring⁸, H J M Groen⁹, F Griesinger¹⁰

Affiliations

¹ Departments of Pulmonary Diseases and Pathology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, p.o. Box 30.000, 9700 RB Groningen, Netherlands; Dept. Hematology and Oncology, Pius-Hospital, University Dept. Internal Medicine-Oncology, Carl von Ossietzky University of Oldenburg, Germany. Electronic address: [email protected].
² Institut für Hämatopathologie Hamburg, Fangdieckstraße 75A, 22547 Hamburg, Germany. Electronic address: [email protected].
³ Institut für Hämatopathologie Hamburg, Fangdieckstraße 75A, 22547 Hamburg, Germany. Electronic address: [email protected].
⁴ Institut für Hämatopathologie Hamburg, Fangdieckstraße 75A, 22547 Hamburg, Germany. Electronic address: [email protected].
⁵ Institut für Hämatopathologie Hamburg, Fangdieckstraße 75A, 22547 Hamburg, Germany. Electronic address: [email protected].
⁶ Department of Internal Medicine and Pulmonology, Asklepios Klinikum Harburg, Eißendorfer Pferdeweg 52, 21075 Hamburg, Germany. Electronic address: [email protected].
⁷ Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. Electronic address: [email protected].
⁸ Departments of Pulmonary Diseases and Pathology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, p.o. Box 30.000, 9700 RB Groningen, Netherlands. Electronic address: [email protected].
⁹ Departments of Pulmonary Diseases and Pathology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, p.o. Box 30.000, 9700 RB Groningen, Netherlands. Electronic address: [email protected].
¹⁰ Dept. Hematology and Oncology, Pius-Hospital, University Dept. Internal Medicine-Oncology, Carl von Ossietzky University of Oldenburg, Germany. Electronic address: [email protected].

PMID: 34673351
DOI: 10.1016/j.prp.2021.153651

Abstract

Immune related endonucleases have recently been described as potential therapeutic targets and predictors of response to treatment with immune checkpoint inhibitors (ICI). The aim is to evaluate the association between the expression of 5 biomarkers involved in the immune response (CD73, CD39, VISTA, Arl4d and Cytohesin-3) in parallel with the more common ICI-predictive markers, PD-L1 expression and Tumor Mutation Burden (TMB) with response to ICI therapy in an advanced non-small cell lung cancer (NSCLC) cohort.

Methods: Patients with advanced NSCLC treated with ICI single agent were divided into responders and non-responders according to RECIST v1.1 and duration of response (DOR) criteria. Immunohistochemistry was performed on pretreatment tumor tissue samples for PD-L1, CD73, CD39, VISTA, Arl4d, and Cytohesin-3 expression. TMB was estimated with NEOplus v2 RUO (NEO New Oncology GmbH) hybrid capture next generation sequencing assay. Resistance mutations in STK11/KEAP1 and positive predictive mutations in ARID1A/POLE were also evaluated.

Results: Included were 56 patients who were treated with ICI single agent. The median progression-free and overall survival for the whole cohort was 3.0 (95% CI, 2.4-3.6) and 15 (95% CI, 9.7-20.2) months, respectively. The distribution of CD73 in tumor cells and CD39, VISTA, Arl4d and Cytohesin-3 expression in immune cells were not different between responders and non-responders. Also, PD-L1 and TMB were not predictive for response. The frequency of STK11, KEAP1 and ARID1A mutations was low and only observed in the non-responder group.

Conclusion: Separate and combined expression of 5 biomarkers involved in the immune response (CD73, CD39, VISTA, Arl4d, and Cytohesin-3) was not associated with response in our cohort of advanced NSCLC patients receiving single agent ICI. To confirm our findings the analysis of independent larger cohorts is warranted.

Keywords: Checkpoint inhibitor; Immunohistochemistry; NSCLC; TMB.

MeSH terms

5'-Nucleotidase / analysis
ADP-Ribosylation Factors / analysis
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized / therapeutic use*
Apyrase / analysis
B7 Antigens / analysis
Biomarkers, Tumor / analysis*
Biomarkers, Tumor / genetics
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / enzymology
Carcinoma, Non-Small-Cell Lung / immunology
Carcinoma, Non-Small-Cell Lung / mortality
Disease Progression
Female
GPI-Linked Proteins / analysis
Humans
Immune Checkpoint Inhibitors / therapeutic use*
Immunohistochemistry
Lung Neoplasms / drug therapy*
Lung Neoplasms / enzymology
Lung Neoplasms / immunology
Lung Neoplasms / mortality
Male
Middle Aged
Mutation
Nivolumab / therapeutic use*
Predictive Value of Tests
Progression-Free Survival
Receptors, Cytoplasmic and Nuclear / analysis
Time Factors

Substances

Antibodies, Monoclonal, Humanized
B7 Antigens
Biomarkers, Tumor
GPI-Linked Proteins
Immune Checkpoint Inhibitors
Receptors, Cytoplasmic and Nuclear
VSIR protein, human
phosphatidylinositol receptors
Nivolumab
pembrolizumab
5'-Nucleotidase
NT5E protein, human
Apyrase
ENTPD1 protein, human
ADP-Ribosylation Factors