postdoctoral fellow, McGill University
Based on 2010 estimates from the Canadian Cancer Society, about 1 in 9 Canadian women is expected to develop breast cancer during her lifetime and 1 in 30 will die from it. Triple Negative Breast Cancers (TNBC) represent 15-20% of all diagnosed breast cancers. TNBCs lack markers amenable to targeted therapies and are associated with poor disease outcome. In TNBC, the presence of CD8+ effector T cells that elicit an anti-tumor immune response correlates with improved outcome; however, patients whose CD8+ T cells are restricted to the tumor periphery generally have poor outcome. Promising novel cancer therapies targeting immune checkpoints (called immunotherapy e.g., PD1/PD-L1) have been developed that boost T cell effector activity. However, only ~20% of TNBC patients respond to anti-PD1/PDL1 therapy, a response that is likely dependent upon both immune cell status and pre-existing infiltration into the tumor bed.
Using our dataset of dissected tumors, I have identified patient subsets that harbour specific features associated with distinct CD8+ T cell localization and activation. Tumors that exhibit CD8+ T cell exclusion from the tumor bed and accumulation at tumor margins are characterized by fibrosis signatures and expression of a distinct negative immune regulator while tumors where CD8+ T cell infiltration is partial are identified by specific metabolic and immunosuppressive signals. Finally, TNBC tumors fully infiltrated by CD8+ T cells are associated with immune activation and expression of common immune checkpoints (e.g. PD-L1). Our TNBC LCM dataset provides us with unique tools to test the hypotheses and validate our preliminary data as follows.
Our work thus further characterized the 3 tumors groups and identified novel features as well as potential biomarkers. Unraveling the mechanisms of resistance to immunotherapy will help us identify ways to sensitize the resistant tumors to this therapy.
Abstract: Although it is increasingly evident that cancer is influenced by signals emanating from tumor stroma, little is known regarding how changes in stromal gene expression affect epithelial tumor progression. We used laser capture microdissection to compare gene expression profiles of tumor stroma from 53 primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumor-derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node-negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.
Pub.: 29 Apr '08, Pinned: 08 Aug '17
Abstract: T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date.Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival.In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37-0.79] versus CD8-negative tumours (HR = 0.87; 95% CI 0.55-1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P heterogeneity = 0.04) and approached significance in imputed data (P heterogeneity = 0.1).The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NEAT ClinicalTrials.gov: NCT00003577.
Pub.: 12 Jun '14, Pinned: 08 Aug '17
Abstract: Publication date: 12 September 2016 Source:Cancer Cell, Volume 30, Issue 3 Author(s): Haidong Tang, Yang Wang, Lukasz K. Chlewicki, Yuan Zhang, Jingya Guo, Wei Liang, Jieyi Wang, Xiaoxiao Wang, Yang-Xin Fu
Pub.: 13 Sep '16, Pinned: 08 Aug '17
Abstract: Multiple independent studies have shown that tumor-infiltrating lymphocytes (TIL) are prognostic in breast cancer with potential relevance for response to immune-checkpoint inhibitor therapy. Although many groups are currently evaluating TIL, there is no standardized system for diagnostic applications. This study reports the results of two ring studies investigating TIL conducted by the International Working Group on Immuno-oncology Biomarkers. The study aim was to determine the intraclass correlation coefficient (ICC) for evaluation of TIL by different pathologists. A total of 120 slides were evaluated by a large group of pathologists with a web-based system in ring study 1 and a more advanced software-system in ring study 2 that included an integrated feedback with standardized reference images. The predefined aim for successful ring studies 1 and 2 was an ICC above 0.7 (lower limit of 95% confidence interval (CI)). In ring study 1 the prespecified endpoint was not reached (ICC: 0.70; 95% CI: 0.62-0.78). On the basis of an analysis of sources of variation, we developed a more advanced digital image evaluation system for ring study 2, which improved the ICC to 0.89 (95% CI: 0.85-0.92). The Fleiss' kappa value for <60 vs ≥60% TIL improved from 0.45 (ring study 1) to 0.63 in RS2 and the mean concordance improved from 88 to 92%. This large international standardization project shows that reproducible evaluation of TIL is feasible in breast cancer. This opens the way for standardized reporting of tumor immunological parameters in clinical studies and diagnostic practice. The software-guided image evaluation approach used in ring study 2 may be of value as a tool for evaluation of TIL in clinical trials and diagnostic practice. The experience gained from this approach might be applicable to the standardization of other diagnostic parameters in histopathology.Modern Pathology advance online publication, 1 July 2016; doi:10.1038/modpathol.2016.109.
Pub.: 02 Jul '16, Pinned: 08 Aug '17