Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non–Small Cell Lung Cancer

Dønnem, Tom; Hald, Sigurd M.; Paulsen, Erna-Elise; Richardsen, Elin; Al-Saad, Samer; Kilvaer, Thomas K.; Brustugun, Odd Terje; Helland, Åslaug; Lund‐Iversen, Marius; Poehl, Mette; Olsen, Karen Ege; Ditzel, Henrik J.; Hansen, Olfred; Al-Shibli, Khalid; Kiselev, Yury; Sandanger, Torkjel M.; Andersen, Sigve; Pezzella, Francesco; Bremnes, Roy M.; Busund, Lill-Tove

doi:10.1158/1078-0432.ccr-14-1905

Cited by 270 publications

(266 citation statements)

References 31 publications

Supporting

Mentioning

239

Contrasting

Unclassified

Order By: Relevance

“…increased CD+8 tiLs have been associated with a better prognosis in many solid neoplasms, including colorectal, melanoma and triplenegative breast carcinoma (4). This study showed that CD8+ tiLs have a significant prognostic effect, as the patients with high CD8+ tiLs gave a partial response to therapy and had a better survival more than those with low CD8+ tiLs; this goes with Donnem et al (13) who found that the stromal CD8+ tiLs density was a strong independent prognostic factor for PFS and OS.…”

Section: Resultssupporting

confidence: 65%

Prognostic significance of programmed cell death ligand 1 (pd-l1), cd8+ tumor-infiltrating lymphocytes and p53 in non-small cell lung cancer: an immunohistochemical study

Rashed

Abdelrahman²,

Abdelgawad³

et al. 2017

TJPATH

View full text Add to dashboard Cite

IntRoduCtIonLung cancer ranks the first in the incidence and mortality rates amongst all malignancies worldwide. Non-small cell lung cancer (NSCLC) constitutes 80% -85% of all diagnosed cases and more than 70% of NSCLC are diagnosed as an advanced or late disease (1).Recognition of tumor antigens by t cells leads to activation of anti-tumor immune reaction mainly by cytotoxic CD+8 tumor infiltrating lymphocytes (tiLs), but malignant cells may have many pathways to evade the immunological destruction. PD-1 is a co-stimulatory molecule on t-cells that inhibits t cell activation. PD-1, which is a 288-amino acid cell-surface protein, can bind two ligands, PD-L1 and PD-L2, which negatively control the immune response. tumor cells express PD-L1 can inhibit t cell-mediated immune response and can progress to distant metastasis (2,3). CD8 marker is expressed on cytotoxic t cells, natural killer, and dendritic cells. CD8+ t cells are a major component of the cell-mediated immune system against malignant cells. CD8+ t cells undergo differentiation to effector cytotoxic t cells. Then the effector CD8+ cells undergo apoptosis leaving memory cells when a pathogenic response is resolved. Memory t cells and cytotoxic t cells are associated with a more favorable prognosis in NSCLC (4).PD-L1 over-expression has been proved to be a poor prognostic marker in many human cancers (5). PD-1/ PD-L1 interaction suppresses CD8+ tiLs survival and proliferation and leads to apoptosis of tumor-infiltrating lymphocytes. PD-L1 over-expression in tumor cells in a syngeneic transplant model of tumor cells makes them evade from cytotoxic tiLs (6). AbStRACtObjective: Programmed cell death ligand-1 interacts with the immune receptors on the surface of CD8+ tumor infiltrating lymphocytes and PD-1, thereby blocking its anti-tumor activity. therapeutics suppression of this interaction will show a promise in the treatment of non-small cell lung cancer by restoring the functional anti-tumor t-cell activity. We aimed to evaluate the association between the immunohistochemical expression of PD-L1, stromal CD8+ tumor infiltrating lymphocytes and p53 with the clinicopathological characteristics, response to chemotherapy, progression-free-survival, and overall survival. Material and Method:We examined the immunohistochemical expression of PD-L1, stromal CD8+ tiLs, and p53 expression in 50 patients with advanced stage (iii&iV) non-small cell lung cancer.Results: PD-L1 was expressed in 56% of the studied cases. PD-L1 expression was related to unfavorable response to the therapy without significant difference. PD-L1 expression was significantly associated with disease progression, poor progression-free-survival & overall survival. CD8+ tiLs were high in 32% of the cases. tumors with high CD8+ tiLs showed a partial response to therapy and had a better progression-free-survival and overall survival. p53 expressed in 82% of the studied cases. there was a significant negative association between PD-L1 and CD8+ tiLs (p=0.009), while a non-significant association wa...

show abstract

Section: Resultssupporting

confidence: 65%

Prognostic significance of programmed cell death ligand 1 (pd-l1), cd8+ tumor-infiltrating lymphocytes and p53 in non-small cell lung cancer: an immunohistochemical study

Rashed

Abdelrahman²,

Abdelgawad³

et al. 2017

TJPATH

View full text Add to dashboard Cite

show abstract

mentioning

confidence: 99%

“…Only two of the previously published similar studies included validation cohorts (12,13). In the study by Donnem et al, one training set and three external validation sets with a total of 797 patients were examined (12). In this study, density of CD8+ T cells was assessed only in stroma as our group previously found stromal CD8+ density (14), rather than within the epithelial cancer cell nests to have significantly stronger prognostic impact with respect to DFS, disease-specific survival (DSS), and OS.…”

mentioning

confidence: 99%

Importance of tumor infiltrating lymphocytes in non-small cell lung cancer?

2016

Self Cite

View full text Add to dashboard Cite

“…CD8+ TIL density has also been evaluated in early stage lung cancer. In a retrospective study of 797 pathologic stage I-IIIA NSCLC, stromal CD8+ TIL density was independently prognostic of disease free survival, disease specific survival, and OS (all P<0.001) (19).…”

Section: Cd8+ Tilsmentioning

confidence: 98%

Beyond PD-L1 testing-emerging biomarkers for immunotherapy in non-small cell lung cancer

et al. 2017

View full text Add to dashboard Cite

Recently, a firmer understanding of tumor immunology and tumor escape mechanisms has led to the development of immune checkpoint inhibitors, antibodies against programmed death-1 (PD-1) and its ligand (PD-L1). Nivolumab, pembrolizumab, and atezolizumab have dramatically altered the treatment paradigm in non-small cell lung cancer (NSCLC) and have each demonstrated improvements in outcomes and quality of life when compared to chemotherapy. Enrichment strategies to better select those patients more likely to respond have identified PD-L1 staining by immunohistochemistry (IHC) to be a predictive biomarker in both treatment naïve and refractory patients. Unfortunately, many challenges exist with this strategy and underscore the need for further exploration for more reliable biomarkers. Multiple tissue and plasma-based enrichment strategies have been identified in the hope of identifying patients more likely to benefit from checkpoint inhibitors. These include tumor mutational load; the "inflamed phenotype" including tumor infiltrating lymphocytes (TILS) and immunoscore; T-cell receptor clonality; gene signatures, and several plasma biomarkers. Several studies have revealed many of these biomarkers to be reliable predictors of response to immune checkpoint inhibitors across multiple tumor types. Given the small nature of these studies, additional prospective studies are warranted to formalize and validate each of these enrichment strategies.

show abstract

Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non–Small Cell Lung Cancer

Cited by 270 publications

References 31 publications

Prognostic significance of programmed cell death ligand 1 (pd-l1), cd8+ tumor-infiltrating lymphocytes and p53 in non-small cell lung cancer: an immunohistochemical study

Prognostic significance of programmed cell death ligand 1 (pd-l1), cd8+ tumor-infiltrating lymphocytes and p53 in non-small cell lung cancer: an immunohistochemical study

Importance of tumor infiltrating lymphocytes in non-small cell lung cancer?

Beyond PD-L1 testing-emerging biomarkers for immunotherapy in non-small cell lung cancer

Contact Info

Product

Resources

About