Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution
Small cell lung cancer (SCLC) has recently been subcategorized into neuroendocrine (NE)‐high and NE‐low subtypes showing ‘immune desert’ and ‘immune oasis’ phenotypes, respectively. Here, we aimed to characterize the tumor microenvironment according to immune checkpoints and NE subtypes in human SCL...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-09-01
|
| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12741 |
| _version_ | 1828791062192193536 |
|---|---|
| author | David Dora Christopher Rivard Hui Yu Paul Bunn Kenichi Suda Shengxiang Ren Shivaun Lueke Pickard Viktoria Laszlo Tunde Harko Zsolt Megyesfalvi Judit Moldvay Fred R. Hirsch Balazs Dome Zoltan Lohinai |
| author_facet | David Dora Christopher Rivard Hui Yu Paul Bunn Kenichi Suda Shengxiang Ren Shivaun Lueke Pickard Viktoria Laszlo Tunde Harko Zsolt Megyesfalvi Judit Moldvay Fred R. Hirsch Balazs Dome Zoltan Lohinai |
| author_sort | David Dora |
| collection | DOAJ |
| description | Small cell lung cancer (SCLC) has recently been subcategorized into neuroendocrine (NE)‐high and NE‐low subtypes showing ‘immune desert’ and ‘immune oasis’ phenotypes, respectively. Here, we aimed to characterize the tumor microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross‐sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early‐stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE‐associated key RNA genes. Immunohistochemistry (IHC) was performed on formalin‐fixed paraffin‐embedded TMAs with antibodies against CD45, CD3, CD8, MHCII, TIM3, immune checkpoint poliovirus receptor (PVR), and indoleamine 2,3‐dioxygenase (IDO). The stroma was significantly more infiltrated by immune cells both in primary tumors and in LN metastases compared to tumor nests. Immune cell (CD45+ cell) density was significantly higher in tumor nests (P = 0.019), with increased CD8+ effector T‐cell infiltration (P = 0.003) in NE‐low vs NE‐high tumors. The expression of IDO was confirmed on stromal and endothelial cells and was positively correlated with higher immune cell density both in primary tumors and in LN metastases, regardless of the NE pattern. Expression of IDO and PVR in tumor nests was significantly higher in NE‐low primary tumors (vs NE‐high, P < 0.05). We also found significantly higher MHC II expression by malignant cells in NE‐low (vs NE‐high, P = 0.004) tumors. TIM3 expression was significantly increased in NE‐low (vs NE‐high, P < 0.05) tumors and in LN metastases (vs primary tumors, P < 0.05). To our knowledge, this is the first human study that demonstrates in situ that NE‐low SCLCs are associated with increased immune cell infiltration compared to NE‐high tumors. PVR, IDO, MHCII, and TIM3 are emerging checkpoints in SCLC, with increased expression in the NE‐low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies. |
| first_indexed | 2024-12-12T02:44:07Z |
| format | Article |
| id | doaj.art-472d643d2641458289ff49cabf44a6e0 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-12T02:44:07Z |
| publishDate | 2020-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-472d643d2641458289ff49cabf44a6e02022-12-22T00:41:05ZengWileyMolecular Oncology1574-78911878-02612020-09-011491947196510.1002/1878-0261.12741Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distributionDavid Dora0Christopher Rivard1Hui Yu2Paul Bunn3Kenichi Suda4Shengxiang Ren5Shivaun Lueke Pickard6Viktoria Laszlo7Tunde Harko8Zsolt Megyesfalvi9Judit Moldvay10Fred R. Hirsch11Balazs Dome12Zoltan Lohinai13Department of Anatomy, Histology and Embryology Faculty of Medicine Semmelweis University Budapest HungaryDivision of Medical Oncology University of Colorado Anschutz Medical Campus Aurora CO USADivision of Medical Oncology University of Colorado Anschutz Medical Campus Aurora CO USADivision of Medical Oncology University of Colorado Anschutz Medical Campus Aurora CO USADivision of Thoracic Surgery Department of Surgery Faculty of Medicine Kindai University Osaka‐Sayama JapanShanghai Pulmonary Hospital Tongji University Shanghai ChinaDivision of Medical Oncology University of Colorado Anschutz Medical Campus Aurora CO USANational Korányi Institute of Pulmonology Budapest HungaryNational Korányi Institute of Pulmonology Budapest HungaryNational Korányi Institute of Pulmonology Budapest HungaryNational Korányi Institute of Pulmonology Budapest HungaryDivision of Medical Oncology University of Colorado Anschutz Medical Campus Aurora CO USANational Korányi Institute of Pulmonology Budapest HungaryNational Korányi Institute of Pulmonology Budapest HungarySmall cell lung cancer (SCLC) has recently been subcategorized into neuroendocrine (NE)‐high and NE‐low subtypes showing ‘immune desert’ and ‘immune oasis’ phenotypes, respectively. Here, we aimed to characterize the tumor microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross‐sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early‐stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE‐associated key RNA genes. Immunohistochemistry (IHC) was performed on formalin‐fixed paraffin‐embedded TMAs with antibodies against CD45, CD3, CD8, MHCII, TIM3, immune checkpoint poliovirus receptor (PVR), and indoleamine 2,3‐dioxygenase (IDO). The stroma was significantly more infiltrated by immune cells both in primary tumors and in LN metastases compared to tumor nests. Immune cell (CD45+ cell) density was significantly higher in tumor nests (P = 0.019), with increased CD8+ effector T‐cell infiltration (P = 0.003) in NE‐low vs NE‐high tumors. The expression of IDO was confirmed on stromal and endothelial cells and was positively correlated with higher immune cell density both in primary tumors and in LN metastases, regardless of the NE pattern. Expression of IDO and PVR in tumor nests was significantly higher in NE‐low primary tumors (vs NE‐high, P < 0.05). We also found significantly higher MHC II expression by malignant cells in NE‐low (vs NE‐high, P = 0.004) tumors. TIM3 expression was significantly increased in NE‐low (vs NE‐high, P < 0.05) tumors and in LN metastases (vs primary tumors, P < 0.05). To our knowledge, this is the first human study that demonstrates in situ that NE‐low SCLCs are associated with increased immune cell infiltration compared to NE‐high tumors. PVR, IDO, MHCII, and TIM3 are emerging checkpoints in SCLC, with increased expression in the NE‐low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies.https://doi.org/10.1002/1878-0261.12741neuroendocrineproteomicsSCLCtumor microenvironmenttumor‐infiltrating immune cells |
| spellingShingle | David Dora Christopher Rivard Hui Yu Paul Bunn Kenichi Suda Shengxiang Ren Shivaun Lueke Pickard Viktoria Laszlo Tunde Harko Zsolt Megyesfalvi Judit Moldvay Fred R. Hirsch Balazs Dome Zoltan Lohinai Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution Molecular Oncology neuroendocrine proteomics SCLC tumor microenvironment tumor‐infiltrating immune cells |
| title | Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution |
| title_full | Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution |
| title_fullStr | Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution |
| title_full_unstemmed | Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution |
| title_short | Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution |
| title_sort | neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution |
| topic | neuroendocrine proteomics SCLC tumor microenvironment tumor‐infiltrating immune cells |
| url | https://doi.org/10.1002/1878-0261.12741 |
| work_keys_str_mv | AT daviddora neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT christopherrivard neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT huiyu neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT paulbunn neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT kenichisuda neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT shengxiangren neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT shivaunluekepickard neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT viktorialaszlo neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT tundeharko neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT zsoltmegyesfalvi neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT juditmoldvay neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT fredrhirsch neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT balazsdome neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution AT zoltanlohinai neuroendocrinesubtypesofsmallcelllungcancerdifferintermsofimmunemicroenvironmentandcheckpointmoleculedistribution |