On-treatment changes in tumor-infiltrating lymphocytes (TIL) during neoadjuvant HER2 therapy (NAT) and clinical outcome.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 574-574 ◽  
Author(s):  
Stephen James Luen ◽  
Gaia Griguolo ◽  
Paolo Nuciforo ◽  
Christine Campbell ◽  
Roberta Fasani ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Immune Cell ◽  
Early Stage ◽  
Tumor Infiltrating Lymphocytes ◽  
Ratio Test ◽  
Cox Models ◽  
Immune Cell Subsets ◽  
Rnaseq Data ◽  
Treatment Changes ◽  
Infiltrating Lymphocytes

574 Background: Higher quantity of pretreatment TIL (PT) is associated with improved pCR and EFS in HER2+ early breast cancer (BC). The value of on-treatment TIL is unknown. Methods: The NeoALTTO trial randomized 455 women with HER2+ BC to 12 weeks NAT with trastuzumab, lapatinib or combination with paclitaxel, followed by FEC after surgery. In the PAMELA trial 151 women received 18 weeks NAT with lapatinib and trastuzumab (±hormonal therapy). TIL were quantified on PT and on-treatment (W2) biopsies using the published method on H&E slides, and tested for associations with pCR (logistic regression), EFS and OS (Cox models) in univariate (UV) and multivariate (MV) analyses. The likelihood ratio test assessed added prognostic value to clinicopathological (CP) variables. pCR associations were validated in PAMELA. We investigated enrichment of immune cell subsets using previously published RNAseq data from NeoALTTO. Results: In NeoALTTO, PT and W2 TIL were evaluable in 277/455 (61%). We defined two groups: immune-poor (L+F) and immune-enriched (II+P), see Table. Immune-enriched (41%; 134) vs poor (59%; 164) patients had significantly higher pCR rates (40% vs 21%; UV OR 2.24; 95%CI 1.31-3.85; P = .003; MV P = .009), and added significant value to CP + PT TIL for prediction of pCR (P = .003). This was further confirmed in PAMELA (N = 94/151) (26% vs 6%; UV P = .021; MV P = .028). In NeoALTTO, the immune-enriched vs poor patients had significantly improved EFS (5 yr est 85% vs 60%; UV HR 0.31; 95%CI 0.18-0.54; P < .001; MV P < .001) and OS (5 yr est 91% vs 77%; UV HR 0.40; 95%CI 0.20-0.82; P = .012; MV P = 0.026), and provided significant added prognostic value beyond CP + pCR + PT TIL (EFS P < .001) In NeoALTTO PT samples, II vs F patients had enrichment of DCs, NKs and CD8+ including tissue resident memory cells (P = .009) suggesting requirement of key immune subsets. Further validation by IHC is ongoing. Conclusions: On-treatment TIL identifies patients more likely to achieve pCR and have improved EFS in early-stage HER2+ BC, beyond CP + PT TIL. This information could aid future trial design. Clinical trial information: NCT00553358, NCT01973660. [Table: see text]

scholarly journals Characterization of Immune Cell Subsets of Tumor Infiltrating Lymphocytes in Brain Metastases

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 425
Author(s):  
Priyakshi Kalita-de Croft ◽  
Haarika Chittoory ◽  
Tam H. Nguyen ◽  
Jodi M. Saunus ◽  
Woo Gyeong Kim ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Tumor Infiltrating Lymphocytes ◽  
Cd8 Cells ◽  
Targeted Analysis ◽  
Immune Cell Subsets ◽  
Checkpoint Molecule ◽  
Formalin Fixed Paraffin Embedded ◽  
Infiltrating Lymphocytes

The heterogeneity of tumor infiltrating lymphocytes (TILs) is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune-cell subsets in brain metastasis tissues to test immunosuppressive routes involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune-cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and IBA-1, and analyzed an average of 15,000 cells per sample. Classifying tumors as either high (>30%) or low (<30%) TILs, we found that increased TILs density correlated with survival. Phenotyping these TILs we found tumors with low TILs had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p < 0.01) as well as in their microenvironment (p < 0.001). Contrastingly, the tumors with high TILs displayed higher levels of microglia, as measured by IBA-1 expression. Low TILs-tumors displayed CD8+ T-cells that co-express VISTA (p < 0.01) significantly more compared to high TILs group, where CD8+cells significantly co-express IBA-11 (p < 0.05). These results were supported by RNA analysis of a publicly available, independent cohort. Our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

scholarly journals Characterisation of Immune Cell Subsets of Tumour Infiltrating Lymphocytes in Brain Metastases

2021 ◽  
Author(s):  
Priyakshi Kalita-de Croft ◽  
Haarika Chittoory ◽  
Tam Nguyen ◽  
Jodi Saunus ◽  
Woo Gyeong Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Brain Metastasis ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Tumor Infiltrating Lymphocytes ◽  
Targeted Analysis ◽  
Immune Cell Subsets ◽  
Tumour Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

The heterogeneity of tumor infiltrating lymphocytes is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune cell subsets in brain metastasis tissues to test which immunosuppressive routes are involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on twenty formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and Iba1, and analyzed an average of 15000 cells per sample. We classified tumours as either high (&gt;30%) or low (&lt;30%) tumour infiltrating lymphocytes (TILs) and found that increased TILs density correlated with survival. We next sought out to phenotype these TILs using mIF. The tumours with low TILs (n=9) had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p&lt;0.01) as well as in their microenvironment (p&lt;0.001). Contrastingly, the brain metastatic tumours with high TILs (n=8) displayed higher levels of activated microglia, as measured by Iba1 expression. Low TILs-tumours displayed CD8+ T-cells that co-express VISTA (p&lt;0.01) significantly more compared to high TILs group, where CD8+ T-cells significantly co-express Iba1 (p&lt;0.05). Interestingly, no definite phenotypes of CD4+ subsets were observed. These results were supported by RNA analysis of a publicly available, independent cohort. In conclusion, our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

scholarly journals Characterisation of immune cell subsets of tumour infiltrating lymphocytes in brain metastases

2021 ◽  
Author(s):  
Priyakshi Kalita-de Croft ◽  
Haarika Chittoory ◽  
Tam Nguyen ◽  
Jodi M Saunus ◽  
Woo Gyeong Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Brain Metastasis ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Tumor Infiltrating Lymphocytes ◽  
Activated Microglia ◽  
Immune Cell Subsets ◽  
Tumour Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

AbstractThe heterogeneity of tumor infiltrating lymphocytes is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune cell subsets in brain metastasis tissues to test which immunosuppressive routes are involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on twenty formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and Iba1, and analyzed an average of 15000 cells per sample. We classified tumours as either high (>30%) or low (<30%) tumour infiltrating lymphocytes (TILs) and found that increased TILs density correlated with survival. We next sought out to phenotype these TILs using mIF. The tumours with low TILs (n=9) had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p<0.01) as well as in their microenvironment (p<0.001). Contrastingly, the brain metastatic tumours with high TILs (n=8) displayed higher levels of activated microglia, as measured by Iba1 expression. Low TILs-tumours displayed CD8+ T-cells that co-express VISTA (p<0.01) significantly more compared to high TILs group, where CD8+ T-cells significantly co-express Iba1 (p<0.05). Interestingly, no definite phenotypes of CD4+ subsets were observed. These results were supported by RNA analysis of a publicly available, independent cohort. In conclusion, our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.Graphical AbstractGraphical abstract:Brain metastasis patients with low TILs have high VISTA expression and patients with high TILs have significantly more activated microglia

scholarly journals Improving Risk Stratification of Early Oral Tongue Cancer with TNM-Immune (TNM-I) Staging System

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3235
Author(s):  
Alhadi Almangush ◽  
Ibrahim O. Bello ◽  
Ilkka Heikkinen ◽  
Jaana Hagström ◽  
Caj Haglund ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tongue Cancer ◽  
Early Stage ◽  
Disease Free Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Staging System ◽  
Oral Tongue ◽  
Oral Tongue Cancer ◽  
Important Player ◽  
Infiltrating Lymphocytes

Although patients with early-stage oral tongue squamous cell carcinoma (OTSCC) show better survival than those with advanced disease, there is still a number of early-stage cases who will suffer from recurrence, cancer-related mortality and worse overall survival. Incorporation of an immune descriptive factor in the staging system can aid in improving risk assessment of early OTSCC. A total of 290 cases of early-stage OTSCC re-classified according to the American Joint Committee on Cancer (AJCC 8) staging were included in this study. Scores of tumor-infiltrating lymphocytes (TILs) were divided as low or high and incorporated in TNM AJCC 8 to form our proposed TNM-Immune system. Using AJCC 8, there were no significant differences in survival between T1 and T2 tumors (p > 0.05). Our proposed TNM-Immune staging system allowed for significant discrimination in risk between tumors of T1N0M0-Immune vs. T2N0M0-Immune. The latter associated with a worse overall survival with hazard ratio (HR) of 2.87 (95% CI 1.92–4.28; p < 0.001); HR of 2.41 (95% CI 1.26–4.60; p = 0.008) for disease-specific survival; and HR of 1.97 (95% CI 1.13–3.43; p = 0.017) for disease-free survival. The TNM-Immune staging system showed a powerful ability to identify cases with worse survival. The immune response is an important player which can be assessed by evaluating TILs, and it can be implemented in the staging criteria of early OTSCC. TNM-Immune staging forms a step towards a more personalized classification of early OTSCC.

scholarly journals Tumor-Infiltrating Lymphocytes in the Tumor Microenvironment of Laryngeal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 486
Author(s):  
Juan P. Rodrigo ◽  
Mario Sánchez-Canteli ◽  
Fernando López ◽  
Gregory T. Wolf ◽  
Juan C. Hernández-Prera ◽  
...  
Keyword(s):  
Systematic Review ◽  
Squamous Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Prognostic Value ◽  
Laryngeal Squamous Cell Carcinoma ◽  
Meta Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

The presence of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment has been demonstrated to be of prognostic value in various cancers. In this systematic review and meta-analysis, we investigated the prognostic value of TIL in laryngeal squamous cell carcinoma (LSCC). We performed a systematic search in PubMed for publications that investigated the prognostic value of TIL in LSCC. A meta-analysis was performed including all studies assessing the association between TIL counts in hematoxylin-eosin (HE)-stained sections, for CD8+ and/or CD3+/CD4+ TIL and overall survival (OS) or disease-free survival (DFS). The pooled meta-analysis showed a favorable prognostic role for stromal TIL in HE sections for OS (HR 0.57, 95% CI 0.36–0.91, p = 0.02), and for DFS (HR 0.56, 95% CI 0.34–0.94, p = 0.03). High CD8+ TIL were associated with a prolonged OS (HR 0.62, 95% CI 0.4–0.97, p = 0.04) and DFS (HR 0.73, 95% CI 0.34–0.94, p = 0.002). High CD3+/CD4+ TIL demonstrated improved OS (HR 0.32, 95% CI 0.16–0.9, p = 0.03) and DFS (HR 0.23, 95% CI 0.10–0.53, p = 0.0005). This meta-analysis confirmed the favorable prognostic significance of TIL in LSCC. High stromal TIL evaluated in HE sections and intra-tumoral and stromal CD3+, CD4+ and/or CD8+ TIL might predict a better clinical outcome.

scholarly journals Prognostic value of CD8CD45RO tumor infiltrating lymphocytes in patients with extrahepatic cholangiocarcinoma

Oncotarget ◽  
2018 ◽  
Vol 9 (34) ◽  
pp. 23366-23372 ◽  
Author(s):  
Richard Kim ◽  
Domenico Coppola ◽  
Emilie Wang ◽  
Young Doo Chang ◽  
Yuhree Kim ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Tumor Infiltrating Lymphocytes ◽  
Extrahepatic Cholangiocarcinoma ◽  
Infiltrating Lymphocytes

Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer

2015 ◽  
Vol 7 (4) ◽  
pp. 232-241
Author(s):  
Koo Si-Lin ◽  
Loh Kiley ◽  
Sulastri Kamis ◽  
Jabed Iqbal ◽  
Rebecca Dent ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Prognostic Value ◽  
Triple Negative ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes
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