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. 2015 Feb 3;107(3):dju435.
doi: 10.1093/jnci/dju435. Print 2015 Mar.

Objective measurement and clinical significance of TILs in non-small cell lung cancer

Kurt A Schalper  1 , Jason Brown  2 , Daniel Carvajal-Hausdorf  2 , Joseph McLaughlin  2 , Vamsidhar Velcheti  2 , Konstantinos N Syrigos  2 , Roy S Herbst  2 , David L Rimm  2
Affiliations

Objective measurement and clinical significance of TILs in non-small cell lung cancer

Kurt A Schalper et al. J Natl Cancer Inst. .

Abstract

Background: Tumor-infiltrating lymphocytes (TILs) are usually measured using subjective methods. Studies suggest that TIL subtypes have independent roles in cancer and that they could support the use of novel immunostimulatory therapies. We simultaneously measured TIL subtypes in non-small cell lung cancer (NSCLC) samples using objective methods and determined their relationship with clinico-pathologic characteristics and survival. VSports手机版.

Methods: Using multiplexed quantitative fluorescence (QIF), we measured the levels of CD3, CD8, and CD20 in 552 NSCLC from two independent collections represented in tissue microarrays (YTMA79, n = 202 and YTMA140, n = 350). The level of TILs was obtained in different tumor compartments using cytokeratin stain to define tumor cells and 4',6-Diamidino-2-Phenylindole. Association of TILs with clinical parameters was determined using univariate and multivariable analyses. All statistical tests were two-sided. V体育安卓版.

Results: In both NSCLC collections there was a low correlation between the three TIL markers (linear regression coefficients (R(2)) = 0. 19-0. 22, P < . 001 for YTMA79 and R(2) = 0. 23-0. 32, P < . 001 for YTMA140). No consistent association between the level of TIL subtypes and age, sex, smoking history, tumor size, stage, and histology type was found. In univariate analysis, an elevated CD3 or CD8 signal was statistically significantly associated with longer survival in both collections. However, only CD8 was independent from age, tumor size, histology, and stage in multivariable analysis V体育ios版. High CD20 was associated with longer survival in the YTMA79 cohort. .

Conclusions: Increased levels of CD3 and CD8 + TILs are associated with better outcome in NSCLC, but only CD8 is independent from other prognostic variables. Objective measurement of TIL subpopulations could be useful to predict response or evaluate the local immune effect of anticancer immune checkpoint inhibitors. VSports最新版本.

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Figures

Figure 1.
Figure 1.
Characterization of tumor-infiltrating lymphocyte (TIL) subpopulations in formalin-fixed paraffin-embedded (FFPE) tissues using multiplexed quantitative immunofluorescence. A-C) Representative microphotographs showing sections from morphologically normal FFPE human tonsil (A) or lung adenocarcinomas (B-C) stained with hematoxylin and eosin (left panels) or with multiple immunofluorescence (right panels). Staining includes CD3 for T lymphocytes (red channel), CD8 for cytotoxic T cells (green), CD20 for B lymphocytes (purple), pancytokeratin for epithelial cells (yellow), and 4’,6-Diamidino-2-Phenylindole for nonselective nuclear staining (blue). The spatial relationship between specific TIL subtypes and tumor or stromal tissue compartments can be appreciated in the multiplexed stain. Bar = 100 µm.
Figure 2.
Figure 2.
Distribution of tumor-infiltrating lymphocyte (TIL) signals in non–small cell lung cancer (NSCLC) samples from two independent populations. Charts showing the distribution of CD3 (red), CD8 (green), and CD20 (purple) quantitative fluorescence (QIF) signal in NSCLC samples from YTMA79 (A) and YTMA140 (B). The relationship between the signal intensity of each marker in the stromal and tumor (cytokeratin positive) compartment is shown in the insets. R2 = Linear regression coefficient. QIF scores are expressed as arbitrary units of fluorescence. AU = arbitrary units of fluorescence; NSCLC = non–small cell lung cancer; QIF = quantitative fluorescence; TIL = tumor-infiltrating lymphocyte.
Figure 3.
Figure 3.
Association between different tumor-infiltrating lymphocyte (TIL) signal and survival in non–small cell lung cancer. A-H) Kaplan-Meier graphical analysis of the overall survival in patients with NSCLC from YTMA79 (A-D) and YTMA140 (E-H) according to CD3 (A and E), CD8 (B and F), CD20 (C and G), or total TILs in hematoxylin and eosin–stained slides (D and H). Case patients with high signal include case patients in the top tertile, and case patients in the low-signal group comprise those in the lower two tertiles (see Methods). The number of patients at risk in each group and the respective log-rank P values are indicated in the chart. All statistical tests were two-sided. H&E = hematoxylin and eosin; TIL = tumor-infiltrating lymphocyte.
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