Prognostic and predictive value of tumor-infiltrating lymphocytes for clinical therapeutic research in patients with non-small cell lung cancer

Zeng, Dongqiang; Yu, Yunfang; Ou, Qiyun; Li, Xiaoyin; Zhong, Ru-Zhi; Xie, Conghua; Hu, Qiugen

doi:10.18632/oncotarget.7282

Cited by 175 publications

(136 citation statements)

References 57 publications

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“…CD4 + T cells were only associated with overall survival when assessed in the tumor stroma rather than the tumor cell nests, while FOXP3 + T regs in the tumor stroma were associated with poorer progression free survival [129]. Sixteen of these studies, along with an additional eight studies, were included in a meta-analysis by Zeng et al [133]. These authors concluded that high levels of CD8 + , CD3 + and CD4 + TILs had prognostic significance for both overall survival and recurrence [133].…”

Section: Tils In Non-small Cell Lung Carcinomamentioning

confidence: 99%

“…Sixteen of these studies, along with an additional eight studies, were included in a meta-analysis by Zeng et al [133]. These authors concluded that high levels of CD8 + , CD3 + and CD4 + TILs had prognostic significance for both overall survival and recurrence [133]. Of note is the moderate to significant heterogeneity identified in both of these meta-analyses, as well as the retrospective nature of the included studies, many of which had incomplete data with regard to important prognostic factors [129,133].…”

Section: Tils In Non-small Cell Lung Carcinomamentioning

confidence: 99%

“…These authors concluded that high levels of CD8 + , CD3 + and CD4 + TILs had prognostic significance for both overall survival and recurrence [133]. Of note is the moderate to significant heterogeneity identified in both of these meta-analyses, as well as the retrospective nature of the included studies, many of which had incomplete data with regard to important prognostic factors [129,133]. In addition, the lack of standardized TILs assessment and arbitrary cut-points may reduce the validity of combining data in this manner.…”

Section: Tils In Non-small Cell Lung Carcinomamentioning

confidence: 99%

See 2 more Smart Citations

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

Hendry

Salgado

Gevaert

et al. 2017

Advances in Anatomic Pathology

607

366

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Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecological system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

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Section: Tils In Non-small Cell Lung Carcinomamentioning

confidence: 99%

Section: Tils In Non-small Cell Lung Carcinomamentioning

confidence: 99%

Section: Tils In Non-small Cell Lung Carcinomamentioning

confidence: 99%

See 1 more Smart Citation

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

Hendry

Salgado

Gevaert

et al. 2017

Advances in Anatomic Pathology

607

366

View full text Add to dashboard Cite

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“…In addition, other components of the tumor microenvironment, such as tumor-infiltrating lymphocytes (TIL), critically contribute to tumor biology and therapeutic response to ICI (24), suggesting that predictive biomarkers aimed at personalized therapy can be obtained by a coordinated multiparametric definition of the immune contexture (24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Low PD-1 Expression in Cytotoxic CD8+ Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value

Mazzaschi

Madeddu

Falco

et al. 2018

Clinical Cancer Research

191

148

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Purpose: The success of immune checkpoint inhibitors strengthens the notion that tumor growth and regression are immune regulated. To determine whether distinct tissue immune microenvironments differentially affect clinical outcome in nonsmall cell lung cancer (NSCLC), an extended analysis of PD-L1 and tumor-infiltrating lymphocytes (TIL) was performed.Experimental Design: Samples from resected adenocarcinoma (ADC 42), squamous cell carcinoma (SCC 58), and 26 advanced diseases (13 ADC and 13 SCC) treated with nivolumab were analyzed. PD-L1 expression and the incidence of CD3, CD8, CD4, PD-1, CD57, FOXP3, CD25, and Granzyme B TILs were immunohistochemically assessed.Results: PD-L1 levels inversely correlated with N involvement, although they did not show a statistically significant prognostic value in resected patients. The incidence and phenotype of TILs differed in SCC versus ADC, in which EGFR and KRAS mutations conditioned a different frequency and tissue localization of lymphocytes. NSCLC resected patients with high CD8 pos lymphocytes lacking PD-1 inhibitory receptor had a longer overall survival (OS: HR ¼ 2.268; 95% CI, 1.056-4.871, P ¼ 0.03). PD-1-to-CD8 ratio resulted in a prognostic factor both on univariate (HR ¼ 1.952; 95% CI, 1.34-3.12, P ¼ 0.001) and multivariate (HR ¼ 1.943; 95% CI, 1.38-2.86, P ¼ 0.009) analysis. Moreover, low PD-1 incidence among CD8 pos cells was a distinctive feature of nivolumab-treated patients, showing clinical benefit with a prolonged progressionfree survival (PFS: HR ¼ 4.51; 95% CI, 1.45-13.94, P ¼ 0.004).Conclusions: In the presence of intrinsic variability in PD-L1 expression, the reservoir of PD-1-negative effector T lymphocytes provides an immune-privileged microenvironment with a positive impact on survival of patients with resected disease and response to immunotherapy in advanced NSCLC.

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“…Both of these studies acknowledged that the relative significance of CD8 T cell infiltration in the center of the tumor versus that of the tumor margin is not yet clear [14, 17]. In addition, associations between CD8 T cell infiltration and survival have varied across multiple studies of human NSCLC [3, 15, 18–24]. …”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of CD8+ tumor-infiltrating lymphocytes in non-small-cell lung cancer: impact on patient prognostic assessments and comparison of quantification by different sampling strategies

Obeid

Wages

et al. 2016

Cancer Immunol Immunother

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Introduction Infiltration of non-small-cell lung cancer (NSCLC) by CD8+ T lymphocytes predicts improved patient survival; however, heterogeneity of intratumoral localization complicates this assessment. Strategies for tumor sampling may not accurately represent the whole tumor. We hypothesized that sampling strategies may alter the identification of tumors with high CD8 density and affect the prognostic significance. Patients and methods Twenty-three primary NSCLC tumors were immunohistochemically stained for CD8 and were assessed using automated software with eight different sampling strategies or the whole tumor. Results of all sampling strategies were compared to the whole tumor counts (paired t tests, Pearson’s r). Associations between CD8 densities and overall survival were assessed (log-rank test). Results Counts from all eight sampling strategies significantly correlated with whole tumor counts (p ≤ 0.001). However, the magnitude of CD8+ cell counts and categorization into high vs low infiltrate groups were affected by the sampling strategy. The most concordant values were derived from random sampling of 20 % of the tumor, a simulated core biopsy, or from sampling the tumor center. TIL infiltration was associated with survival when sampling the center (p = 0.038), but not the invasive margin (p > 0.2) or other strategies. Conclusion Different tumor sampling strategies may yield discordant TIL density results and different stratification for risk assessment. Small biopsies may be particularly unrepresentative. Random sampling of larger tumor areas is recommended. Enumerating CD8+ T cells in the tumor center may have prognostic value.

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Prognostic and predictive value of tumor-infiltrating lymphocytes for clinical therapeutic research in patients with non-small cell lung cancer

Cited by 175 publications

References 57 publications

Low PD-1 Expression in Cytotoxic CD8+ Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value

Heterogeneity of CD8+ tumor-infiltrating lymphocytes in non-small-cell lung cancer: impact on patient prognostic assessments and comparison of quantification by different sampling strategies

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