Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases

The immune microenvironment of the brain differs from that of other organs and the role of tumor-infiltrating lymphocytes (TILs) in brain metastases (BM), one of the most common and devastating complication of cancer, is unclear. We investigated TIL subsets and their prognostic impact in 116 BM specimens using immunohistochemistry for CD3, CD8, CD45RO, FOXP3, PD1 and PD-L1. The Immunoscore was calculated as published previously. Overall, we found TIL infiltration in 115/116 (99.1%) BM specimens. PD-L1 expression was evident in 19/67 (28.4%) BM specimens and showed no correlation with TIL density (p > 0.05). TIL density was not associated with corticosteroid administration (p > 0.05). A significant difference in infiltration density according to TIL subtype was present (p < 0.001; Chi Square); high infiltration was most frequently observed for CD3+ TILs (95/116; 81.9%) and least frequently for PD1+ TILs (18/116; 15.5%; p < 0.001). Highest TIL density was observed in melanoma, followed by renal cell cancer and lung cancer BM (p < 0.001). The density of CD8+ TILs correlated positively with the extent of peritumoral edema seen on pre-operative magnetic resonance imaging (p = 0.031). The density of CD3+ (15 vs. 6 mo; p = 0.015), CD8+ (15 vs. 11 mo; p = 0.030) and CD45RO+ TILs (18 vs. 8 mo; p = 0.006) showed a positive correlation with favorable median OS times. Immunoscore showed significant correlation with survival prognosis (27 vs. 10 mo; p < 0.001). The prognostic impact of Immunoscore was independent from established prognostic parameters at multivariable analysis (HR 0.612, p < 0.001). In conclusion, our data indicate that dense TILs infiltrates are common in BM and correlate with the amount of peritumoral brain edema and survival prognosis, thus identifying the immune system as potential biomarker for cancer patients with CNS affection. Further studies are needed to substantiate our findings.

[1]  M. Weller,et al.  Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. , 2015, Neuro-oncology.

[2]  G. Ricken,et al.  Tumour‐infiltrating lymphocytes and expression of programmed death ligand 1 (PD‐L1) in melanoma brain metastases , 2015, Histopathology.

[3]  Molin Wang,et al.  Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  G. Ricken,et al.  1324PTUMOR-INFILTRATING LYMPHOCYTES (TILS) AND PD-L1 EXPRESSION IN NON- SMALL CELL LUNG CANCER BRAIN METASTASES (BM) AND MATCHED PRIMARY TUMORS (PT). , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  J. Taube,et al.  Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy , 2014, Clinical Cancer Research.

[6]  W. Wick,et al.  Microenvironmental Clues for Glioma Immunotherapy , 2014, Current Neurology and Neuroscience Reports.

[7]  F. Marincola,et al.  Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours , 2013, The Journal of pathology.

[8]  Frank Winkler,et al.  Invasion patterns in brain metastases of solid cancers. , 2013, Neuro-oncology.

[9]  Jérôme Galon,et al.  The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. , 2013, Immunity.

[10]  A. Woehrer.  Brain tumor epidemiology in Austria and the Austrian Brain Tumor Registry. , 2013, Clinical neuropathology.

[11]  J. Pichler,et al.  Extent of peritumoral brain edema correlates with prognosis, tumoral growth pattern, HIF1a expression and angiogenic activity in patients with single brain metastases , 2012, Clinical and Experimental Metastasis.

[12]  Stefan Michiels,et al.  Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  F. Marincola,et al.  Cancer classification using the Immunoscore: a worldwide task force , 2012, Journal of Translational Medicine.

[14]  David C. Smith,et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. , 2012, The New England journal of medicine.

[15]  J. Wolchok,et al.  Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. , 2012, The Lancet. Oncology.

[16]  C. Sautès-Fridman,et al.  The immune contexture in human tumours: impact on clinical outcome , 2012, Nature Reviews Cancer.

[17]  F. Marincola,et al.  The immune score as a new possible approach for the classification of cancer , 2012, Journal of Translational Medicine.

[18]  R. Palmqvist,et al.  Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor , 2011, Modern Pathology.

[19]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[20]  Zlatko Trajanoski,et al.  Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  G. Pantaleo,et al.  Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells , 2010, Proceedings of the National Academy of Sciences.

[22]  H. Heinzl,et al.  The Austrian Brain Tumour Registry: a cooperative way to establish a population-based brain tumour registry , 2009, Journal of Neuro-Oncology.

[23]  Soldano Ferrone,et al.  HLA Class I Antigen Processing Machinery Component Expression and Intratumoral T-Cell Infiltrate as Independent Prognostic Markers in Ovarian Carcinoma , 2008, Clinical Cancer Research.

[24]  Walter Curran,et al.  A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. , 2008, International journal of radiation oncology, biology, physics.

[25]  Z. Trajanoski,et al.  Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome , 2006, Science.

[26]  Z. Trajanoski,et al.  Effector memory T cells, early metastasis, and survival in colorectal cancer. , 2005, The New England journal of medicine.

[27]  W. Sauerbrei,et al.  Confidence intervals for the effect of a prognostic factor after selection of an ‘optimal’ cutpoint , 2004, Statistics in medicine.

[28]  E. Gilboa,et al.  RG-2 glioma growth attenuation and severe brain edema caused by local production of interleukin-2 and interferon-gamma. , 1995, Cancer research.

[29]  W. Sauerbrei,et al.  Dangers of using "optimal" cutpoints in the evaluation of prognostic factors. , 1994, Journal of the National Cancer Institute.

[30]  V. Perry,et al.  What is immune privilege (not)? , 2007, Trends in immunology.