Immune Cell Infiltration May Be a Key Determinant of Long-Term Survival in Small Cell Lung Cancer

Muppa, Prasuna; Terra, Simone; Sharma, Anurag; Mansfield, Aaron S.; Aubry, Marie Christine; Bhinge, Kaustubh N.; Asiedu, Michael K.; Andrade, Mariza de; Janaki, Nafiseh; Murphy, Stephen J.; Nasir, Aqsa; Keulen, Virginia Van; Vasmatzis, George; Wigle, Dennis A.; Yang, Ping; Yi, Eunhee S.; Peikert, Tobias; Kosari, Farhad

doi:10.1016/j.jtho.2019.03.028

Cited by 83 publications

(60 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The exploration of the tumor microenvironment as a prognostic and diagnostic biomarker or therapy target is an area of active research [36]. Some studies have shown that immune cell infiltration has an influence on survival in lung cancer [37,38]. Other significant findings of the present study are that CLEC3B plays a role in tumor-immune interactions and that CLEC3B expression is correlated with the immune infiltration level in lung cancer, especially in SCC.…”

Section: Figsupporting

confidence: 54%

CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment

et al. 2020

View full text Add to dashboard Cite

Background: Lung cancer is the leading cause of cancer-related mortality globally. Discovering effective biomarkers for early diagnosis and prognosis is important to reduce the mortality rate and ensure efficient therapy for lung cancer patients. C-type lectin domain family 3 member B (CLEC3B) has been reported in various cancers, but its correlation with lung cancer remains elusive. Methods:The GEO, TCGA and Oncomine databases were analyzed to examine the expression of CLEC3B in lung cancer. The CLEC3B mRNA levels in 15 patient tissue samples were detected by real-time PCR and the CLEC3B protein levels in 34 patient tissue samples were detected by immunohistochemistry. A Chi-square test was performed to analyze the correlation of CLEC3B expression and clinicopathological factors. The diagnostic value of CLEC3B was revealed by receiver operating characteristic (ROC) curves. Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier plots were used to evaluate the prognostic value of CLEC3B in lung cancer. The TIMER database was used to evaluate the correlation of CLEC3B and immune infiltration. Gene set enrichment analysis revealed tumor-associated biological processes related to CLEC3B.Results: CLEC3B is significantly downregulated in lung cancer patients compared with nontumor controls according to database analysis and patient tissue sample detection (p < 0.001). Specifically, CLEC3B is significantly downregulated in stage IA lung cancer patients (p < 0.001) and has a high diagnostic accuracy (area under the receiver operating characteristic curve > 0.9). Moreover, low expression of CLEC3B is related to poor progression-free survival (HR = 0.60, 95% CI 0.49-0.74, p = 8.3e−07) and overall survival (HR = 0.66, 95% CI 0.58-0.75, p = 2.1e−10), indicating it as a risk factor for lung cancer. Multivariate analysis value showed that low expression of CLEC3B may be an independent risk factor for disease-free survival in lung cancer patients (HR = 0.655, 95% CI 0.430-0.996, Cox p = 0.048). In addition, we also investigated the potential role of CLEC3B in tumor-immune interactions and found that CLEC3B might be associated with the immune infiltration and immune activation of lung cancer, especially in squamous cell carcinoma.© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article'

show abstract

Section: Figsupporting

confidence: 54%

CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Nevertheless, the latest SCLC clinical studies showed no difference in intraepithelial CD3+ infiltration between patients with shorter vs. longer survival. However, significantly higher CD3+ infiltration in the stroma and at the cell-cell interface was present among patients with more prolonged survival (Muppa et al, 2019). Immune response evasion by tumors may play a crucial role in the aggressiveness of SCLC, and can be due to the insufficient number of T cells or T cells that are inhibited in the tumor microenvironment (Antonia et al, WCLC 2019).…”

Section: I and J)mentioning

confidence: 99%

“…Others showed that the extent of immunological infiltration in tumor tissue and the expression of immune checkpoints proved to be a reliable marker for response to anti-PD immunotherapy and long term survival in SCLC (Muppa et al, 2019;Bonanno et al, 2018); NSCLC , and other malignancies, like breast cancer (Bates et al, 2006), melanoma (Clemente et al, 1996), colorectal carcinoma (Galon et al, 2006), and prostatic cancer (Vesalainen et al, 1994) as well. Another group indicated on NSCLC TMA samples that a high number of stromal CD4+ and epithelial and stromal CD8+ cells were independent positive prognostic markers, and CD8+ Tumor-Infiltrating Lymphocytes (TILs) can stratify immunotherapy-treated patients of different clinical outcome (Lin Z et al, 2019).…”

mentioning

confidence: 99%

Small Cell Lung Cancer Neuroendocrine Subtypes are Associated with Different Immune Microenvironment and Checkpoint Molecule Distribution

Dóra

Rivard

et al. 2020

Preprint

View full text Add to dashboard Cite

The authors thank the patients and the clinical teams involved. We thank Leslie Rozeboom for her assistance in creating TMA blocks. ABSTRACTSmall cell lung cancer (SCLC) has recently been sub-categorized into neuroendocrine (NE)high and NE-low subtypes showing 'immune desert' and 'immune oasis' phenotypes, respectively. We aimed to characterize the immune cell localization and the 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 FFPE TMAs with antibodies against CD45, CD3, CD8 and immune checkpoints including poliovirus receptor (PVR) and Indoleamine 2,3-dioxygenase (IDO).According to our results, the stroma was significantly more infiltrated by immune cells both in primary tumors and LN metastases (vs tumor cell nests). Immune (CD45+) cell density was significantly higher in tumor nests (110.6 ± 24.95 vs 42.74 ± 10.30, cell/mm2, p= 0.0048), with increased CD8+ effector T cell infiltration (21.81 ± 5.458 vs 3.16 ± 1.36 cell/ mm2, p < 0.001) in NE-low vs NE-high tumors. Furthermore, the expression of IDO was 3 confirmed on stromal and endothelial cells, and it positively correlated (r= 0.755, p<0.01) with higher immune cell density both in primary tumors and LN metastases, regardless of the NE pattern. Expression of IDO in tumor nests was significantly higher in NE-low (vs NEhigh) primary tumors. PVR expression was significantly higher in NE-low (vs NE-high) patients both in primary tumors) and LN metastases.To our knowledge, this is the first human study that demonstrates in situ that NE-low tumors are associated with increased immune cell infiltration compared to NE-high tumors. PVR and IDO are potential new targets 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.

show abstract

“…We have read with interest the article by Muppa et al 1 about the potential importance of immune cell infiltration for long-term survivorship (LTS) in patients with SCLC. Through comparing the differentially expressed genes between patients with LTS and patients with short-term survivorship, the authors found enriched numbers of tumor-infiltrating and associated lymphocytes in tumors in patients with LTS.…”

Section: To the Editormentioning

confidence: 99%

“…Recently, Boothman et al demonstrated that several clinical factors, such as the storage time of the paraffin specimen and prior chemoradiotherapy, result in significantly enhanced tumor expression of programmed death ligand 1. 2 The samples from patients with SCLC that were screened in the study by Muppa et al 1 were mainly taken from the archival formalin-fixed paraffin embedded surgical tissue specimens (sample age >3 months). The fresh biopsy specimens should be reanalyzed to provide a more accurate assessment of current immune cell profiling in individual SCLC tumors.…”

Section: To the Editormentioning

confidence: 99%

Immune Cell Infiltration Influences Long-Term Survivorship of Patients with SCLC

Yan

Liu

et al. 2019

Journal of Thoracic Oncology

View full text Add to dashboard Cite

Immune Cell Infiltration May Be a Key Determinant of Long-Term Survival in Small Cell Lung Cancer

Cited by 83 publications

References 21 publications

CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment

CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment

Small Cell Lung Cancer Neuroendocrine Subtypes are Associated with Different Immune Microenvironment and Checkpoint Molecule Distribution

Immune Cell Infiltration Influences Long-Term Survivorship of Patients with SCLC

Contact Info

Product

Resources

About