Prognostic Value Of Tumor-infiltrating Lymphocytes Research Articles

Prognostic Value of Tumor-Infiltrating Lymphocytes for Patients With Head and Neck Squamous Cell Carcinoma

BACKGROUND: The prognostic value of tumor-infiltrating lymphocytes (TILs) in head and neck squamous cell carcinoma (HNSCC) remains controversial. Additionally, there is no standardized approach or cutoff value for evaluating TIL levels. The aim of this study was to establish a feasible method and criterion to assess TIL levels for future clinical practice and research use and to explore the relationship between TIL levels and prognosis. PATIENTS AND METHODS: This retrospective cohort study reviewed the records and pathological sections of 202 patients with HNSCC who were surgically treated at Beijing Stomatological Hospital, Capital Medical University, from January 1998 to January 2011. The predictor variable was the TIL level. The main outcome assessment parameters were disease-free survival (DFS) and disease-specific survival (DSS). RESULT: The T stage (P = .008), smoking history (P = .042), alcohol history (P = .048), need for radiotherapy (P = .012) and microscopic extracapsular spread (ECS) (P = .012) were associated with the TIL level. A cutoff value equal to 70% could be taken as a threshold for TIL assessment, with a TIL level higher than 70% associated with a better prognosis (DFS rate: 51.9%, P = .018; DSS rate: 59.3%, P = .049). The Cox regression model showed that the TIL level was an independent prognostic factor for DFS (hazard ratio (HR): 0.786, 95% CI: 0.618-0.999, P = .049). CONCLUSION: The TIL level is closely related to the prognosis of patients with HNSCC. A threshold value of 70% is appropriate for TIL assessment, as patients with a TIL level higher than 70% show a better prognosis. Thus, the TIL level might serve as an independent predictor for HNSCC recurrence.

Application of the Immunoscore as prognostic tool for hepatocellular carcinoma

To date, the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) tumor, nodes, metastasis (TNM) classification represents the standard system for evaluation of prognosis...

Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer

T-cell infiltration in tumors has been used as a prognostic tool in non-small-cell lung cancer (NSCLC). However, the influence of smoking habit and histological type on tumor-infiltrating lymphocytes (TILs) in NSCLC remains unclear. We evaluated the prognostic significance of TILs (CD4+, CD8+, CD20+, and FOXP3+) according to histological type and smoking habit using automatic immunohistochemical staining and cell counting in 218 patients with NSCLC. In multivariate survival analyses of clinical, pathological, and immunological factors, a high ratio of FOXP3+ to CD4+ T cells (FOXP3/CD4) [hazard ratio (HR): 4.46, P < 0.01 for overall survival (OS); HR: 1.96, P < 0.05 for recurrence-free survival (RFS)] and a low accumulation of CD20+ B cells (HR: 2.45, P = 0.09 for OS; HR: 2.86, P < 0.01 for RFS) were identified as worse prognostic factors in patients with adenocarcinoma (AD). In non-AD, a low number of CD8+ T cells were correlated with an unfavorable outcome (HR: 7.69, P < 0.01 for OS; HR: 3.57, P < 0.02 for RFS). Regarding smoking habit in AD, a high FOXP3/CD4 ratio was poorly prognostic with a smoking history (HR: 5.21, P < 0.01 for OS; HR: 2.38, P < 0.03 for RFS), whereas a low accumulation of CD20+ B cells (HR: 4.54, P = 0.03 for OS; HR: 2.94, P < 0.01 for RFS) was confirmed as an unfavorable factor in non-smokers with AD. A low number of CD8+ T cells in non-AD, a high FOXP3/CD4 ratio in smokers with AD, and a low number of CD20+ B cells in non-smokers with AD were identified as independent unfavorable prognostic factors in resected NSCLC. Evaluating the influence of histological type and smoking habit on the immunological environment may lead to the establishment of immunological diagnosis and appropriate individualized immunotherapy for NSCLC.

Regulatory T cells, especially ICOS+ FOXP3+ regulatory T cells, are increased in the hepatocellular carcinoma microenvironment and predict reduced survival.

Hepatocellular carcinoma (HCC) is a common malignant tumour, especially in Asia. Its prognosis is poor, and there are limited methods for predicting patient survival. This study was carried out to analyse the prognostic value of tumour-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in HCC patients. TILs were analysed in 57 randomly selected HCC patients. The prognostic effects of groups with high and low numbers were evaluated by the Kaplan-Meier and Cox model analyses. Although higher densities of CD3+, CD4+, and CD8+ cytotoxic lymphocytes (CTLs) as well as CD56+ NK cells and CD68+ macrophages were observed in peritumoural tissue, increased numbers of forkhead/winged helix transcription factor P3+ (FOXP3+) Tregs were found in intratumoural tissue. Additionally, regarding ICOS+ FOXP3+ Tregs, an increased prevalence in carcinoma was not only associated with the absolute number but also with the percentage of FOXP3+ cells. Higher Treg levels in tumour tissues indicated a worse prognosis, and the FOXP3+ Tregs/CD4+ T cells ratio was an independent prognostic factor for OS. Therefore, FOXP3+ Tregs, especially ICOS+ FOXP3+ Tregs, contribute to the immunosuppressive HCC microenvironment. High tumour-infiltrating Tregs are thought to be an unfavourable prognostic indicator of HCC.

F27 - Tumor infiltrating lymphocytes in triple negative breast cancer and correlations with prognosis

Background: Following the development of drugs reactivating the immune system, the need to identify immunological markers that can provide prognostic and predictive information is rapidly increasing. This is mainly relevant in triple negative breast cancers, due to their immunogenic potential. Tumor infiltrating lymphocytes (TILs) have been claimed as possible biomarkers of such immune activation, and we investigated their correlation with prognosis. Material and methods: We retrospectively quantified the stromal TILs in 71 triple negative breast cancer patients (pts) surgically treated. TILs were stained with hematoxylin and eosin and were analyzed according to recommendations of TILs Working Group Consensus. TILs were classified as low if ≤ 10% (L-TILs), as intermediate between 10 and 40% (I-TILs) and as high if > 40% (H-TILs). TILs subsets were correlated with TNM stage, proliferative activity, vascular invasion, adjuvant treatment and disease outcome (DFS and OS). Finally we analyzed the influence of TILs on DFS and OS in 43 TN pts with very bad prognostic factors, defined as pT > 5 cm, pN ≥ 2, presence of vascular invasion and proliferative activity ≥ 70%. Results: Twenty-two pts had L-TILs (31%), 13 pts I-TILs (18.3%) and 36 pts had H-TILs (50.3%). Seventeen pts (23.9%) had disease recurrence, 8 of which at nervous central system. Among TILs subgroups, disease progression occurred more frequently in L-TILs pts (63.6% (mDFS), and in I-TILs (53.8%) than in H-TILs (7.3%). Median DFS was 15.1 mos (95%IC 9.7-20.5) in L-TILs, 56.3 mos (26.5-86.1 mos) in I-TILs and was not reached in H-TILs. Similarly, mOS was 29.3 mos in L-TILs, 74.1 mos in I-TILs and not reached in H-TILs (p < 0.0001). Multivariate analysis showed that TILs subsets constitute an independent prognostic factor for both DFS (HR 0.343, p = 0.006) and OS (HR 0.475, p = 0.009). Also among the 43 TN pts with bad prognostic factors, 66.7% in L-TILs pts showed disease progression, 62.5% in I-TILs pts and 0% in H-TILs pts (p < 0.0001). Conclusions: Our study confirms that stromal TILs subsets, evaluated with hematoxylin and eosin, are independent prognostic factors in triple negative breast cancer patients, with H-TILs subset being associated with a favourable outcome. Moreover, the prognostic value of TILs is maintained even in pts with more unfavorable prognosis, based on classical clinico-pathological features. The adjuvant strategy in TN breast cancer with H-TILs should be re-evaluated.

The Prognostic Value of Tumor-Infiltrating Lymphocytes in Breast Cancer: A Systematic Review and Meta-Analysis.

BackgroundThe prognostic values of tumor-infiltrating lymphocytes (TILs) and TILs subsets in breast cancer (BC) are uncertain.MethodsA systematic literature search (MEDLINE, Web of Science, EMBASE, and the Cochrane Library to August 2014) was conducted for studies which met the eligibility criteria. The primary clinical outcome was defined as disease-free survival (DFS), overall survival (OS), and BC-specific survival (BCSS). Random or fixed-effects model was adopted to estimate the summary hazard ratio (HR).ResultsTwenty-five published studies comprising 22,964 patients were reviewed. Pooled analysis indicated that TILs were not prognostic markers for DFS and OS in overall population, but related to improved DFS (HR, 0.82; 95% CI, 0.76–0.88) and OS (HR, 0.79; 95% CI, 0.71–0.87) in triple negative breast cancer (TNBC) patients. For TILs subsets, CD8+ lymphocytes were associated with improved DFS (HR, 0.69; 95% CI, 0.56–0.84) and BCSS (HR, 0.78; 95% CI, 0.71–0.86) in overall population, while FOXP3+ lymphocytes were associated with reduced DFS (HR, 1.47; 95% CI, 1.01–2.05) and OS (HR, 1.50; 95% CI, 1.15–1.97). In estrogen receptor (ER) negative patients, CD8+ lymphocytes was also related to better BCSS. In addition, the high density of CD20+, CD3+ or low level of PD-1+ or γδ T lymphocytes indicated increased OS in limited studies.ConclusionTILs and TILs subsets are promising prognostic biomarkers in breast cancer, especially in TNBC.

Prognostic value of tumor-infiltrating lymphocytes in Epstein–Barr virus-associated gastric cancer

This study explored the prognostic impact of tumor-infiltrating lymphocytes (TILs) and investigated whether three histologic subtypes (lymphoepithelioma-like carcinoma, carcinoma with Crohn's disease-like lymphoid reaction, and conventional-type adenocarcinoma) could stratify a prognostic subset for patients with Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC). After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, 120 patients were identified as EBV-positive using EBV-encoded RNA in situ hybridization. The evaluation of the percentage of intratumoral (iTu-) and stromal (str-) TILs was carried out, and the cases were also subclassified into three histologic subtypes as noted above. Among the 120 patients, 73 patients (60.8%) and 60 patients (50.0%) were determined as str-TIL-positive and iTu-TIL-positive, respectively. In a univariate analysis, str-TIL-positivity was significantly associated with longer recurrence-free survival (RFS; P = 0.002) and disease-free survival (DFS; P = 0.008), yet not overall survival (OS; P = 0.145). While iTu-TIL-positivity has a tendency of favorable outcome indicator for DFS and OS, but statistically significant differences were not shown, respectively (RFS, P = 0.058; DFS, P = 0.151; OS, P = 0.191). In a multivariate analysis using a Cox proportional hazard model adjusted for age, pTNM stage, lymphatic invasion, perineural invasion, and venous invasion; histologic subtype, WHO classification, and str-TIL-positivity were independently or tentatively associated with favorable RFS (hazard ratio [HR] = 12.193, 95% confidence interval [95% CI] 1.039-143.055, P = 0.047) or DFS (HR = 4.836, 95% CI 0.917-25.525, P = 0.063). The histologic subclassification and TILs can be used to predict RFS and DFS for patients with EBVaGC.

Abstract P4-14-17: Prognostic value of tumor-infiltrating lymphocytes in residual tumors after neoadjuvant chemotherapy concomitant with trastuzumab for HER2-positive breast cancer

Abstract Background: Neoadjuvant chemotherapy (NAC) with taxanes, followed by fluorouracil, epirubicin, and cyclophosphamide (FEC), with concurrent trastuzumab is known to achieve a high pCR rate of more than 60% for HER2-positive breast cancer (BC) as well as good prognoses in those obtaining pCR. On the other hand, the prognostic significance of tumor-infiltrating lymphocytes (TILs) has recently been described in triple-negative BC. However, the prognostic and predictive values of TILs in HER2-positive BC remain unclear. In the present study, we examined the grades of TILs in pre-treatment cancer tissues and residual tumors after NAC with trastuzumab, and also investigated its predictive utility for pCR and prognostic power for HER2-positive BC. Patients and Methods: A total of 128 Japanese women with HER2-positive BC received either paclitaxel or docetaxel followed by FEC, with concomitant trastuzumab. The proportional grades of stromal (Str)-TILs in pre-treatment biopsy specimens and residual tumors after NAC with trastuzumab were determined as follows: low grade (0-10%), intermediate grade (10-40%), and high grade (40-90%), using the criteria of the International Working Group for TILs in BC. Analysis 1: The relationship between the grades of Str-TILs in pre-treatment tumors and pCR rates was investigated. Relapse-free survival (RFS) and cancer-specific survival (CSS) were analyzed for a correlation with pre-treatment Str-TILs. Analysis 2: Alterations in the grade of Str-TILs were examined in the residual tumors of non-pCR patients, and RFS and CSS were analyzed for a correlation with residual Str-TILs. Results: pCR was achieved in 83 out of the 128 patients (pCR rate, 64.8%) who received NAC with trastuzumab, and RFS was significantly better in the pCR group than in the non-pCR group (p = 0.0071). Analysis 1: The patient distribution of the Str-TILs grade in pre-treatment tumors was as follows: high: 24 (18.8%); intermediate: 38 (29.7%); and low: 66 (51.6%). pCR rates correlated with the Str-TILs grade in pre-treatment tumors: 83.3% in the high group, 71.1% in the intermediate group, and 54.5% in the low group (p = 0.026); however, the Str-TILs grade in pre-treatment tumors did not correlate with survival. Analysis 2: In 45 non-pCR patients, the distribution of the Str-TILs grade in residual tumors was as follows: high: 9 (20.0%); intermediate: 8 (17.8%); and low: 28 (62.2%), respectively. In non-pCR patients, the rate of a high Str-TILs grade was greater in residual tumors than in pre-treatment tumors (residual, 20.0%, pre-treatment, 8.9%). RFS was significantly better with a high grade than with a low grade of residual Str-TILs (p = 0.033). Conclusions: The status of TILs in pre-treatment tumors predicted responses to NAC concomitant with trastuzumab in HER2-positive BC. The grade of TILs was higher in residual tumors than in pre-treatment tumors, and, among non-pCR patients, the prognosis of patients with a high residual-TILs grade was better prognosis than that of patients with a low residual-TILs grade. We speculate that an examination of TILs in residual tumors after NAC with trastuzumab may be necessary for selecting patients with a good prognosis from non-pCR patients. Citation Format: Kurozumi S, Inoue K, Matsumoto H, Hayashi Y, Tozuka K, Kubo K, Komatsu K, Takai K, Nagai SE, Oba H, Horiguchi J, Takeyoshi I, Kurosumi M. Prognostic value of tumor-infiltrating lymphocytes in residual tumors after neoadjuvant chemotherapy concomitant with trastuzumab for HER2-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-17.

Abstract P4-04-06: Immune balance between tumor-infiltrating lymphocytes and tumor-associated macrophages impacts the outcome of triple negative breast cancer patients

Abstract Background: Stromal tumor-infiltrating lymphocytes (TILs) are emerging as a robust prognostic factor in triple negative breast cancer (TNBC). However, the prognostic value of TILs may be also influenced by the complex landscape of the tumor immune microenvironment. In this study, we aimed to assess the correlation between TILs and tumor-associated macrophages with pro-tumoral functions (M2 TAMs), and to determine the prognostic role of TAM/TIL ratio in TNBC. Methods: Formalin-fixed, paraffin-embedded tissues were retrospectively collected from 189 patients with histologically confirmed invasive ductal TNBC. Stromal TILs were evaluated on H&amp;E slides. The content of CD163-positive M2 TAMs in tumor stroma was assessed by immunohistochemistry. Whole tumor slides were independently assessed by two pathologists blinded for patient characteristics and outcome. CD163 staining was dichotomized into absent/moderate or dense infiltration; 50% stromal TILs was used as threshold (Salgado, 2015). Statistical analyses were performed using Spearman's correlation, Fisher's exact tests, Kaplan-Meier and Cox regression analyses. Results: TNBC patients treated with adjuvant chemotherapy who experienced tumor recurrence showed a significant lower content of stromal TILs (p &amp;lt; 0.0001) and a higher infiltration of CD163-positive TAMs (p = 0.020) compared to patients without recurrence. Stromal TILs were also associated with lymph node positivity (p = 0.036). Univariate and multivariate analysis confirmed the importance of stromal TILs as a prognostic marker of recurrence-free survival (RFS), and overall survival (OS). Importantly, we found that stromal TILs inversely correlated with CD163-positive TAMs (rs = -0.539; p &amp;lt; 0.0001), indicating the significance of the balance between distinct immune components in the tumor microenvironment. Consistently, TNBC patients with a high TAM/TIL ratio had significantly shorter RFS (Log-rank p &amp;lt; 0.0001) and OS (Log-rank p &amp;lt; 0.0001) than patients with low TAM/TIL ratio. TAM/TIL ratio also retained its independent prognostic significance for RFS (HR = 7.02; 95%CI 2.09 - 23.59, p = 0.002) and OS (HR = 7.11; 95%CI 2.10 - 24.05, p = 0.002) in multivariate analysis. Conclusions: Distinct immune cell subpopulation may have a specific role in modulating the immune response against breast tumor. A high content of TAMs with pro-tumoral functions may influence the recruitment of lymphocytes and suppress antitumor immunity. Indeed a high TAM/TIL ratio could help to identify a subset of TNBC patients at high risk for relapse and reduced OS. The understanding of the biological and clinical relevance of immune balance in tumor microenvironment warrants further investigations, and may be useful for the stratification of TNBC patients who may benefit from the addition of immunomodulatory therapies. Citation Format: Bottai G, Raschioni C, Losurdo A, Di Tommaso L, Roncalli M, Santarpia L. Immune balance between tumor-infiltrating lymphocytes and tumor-associated macrophages impacts the outcome of triple negative breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-04-06.

Prognostic value of tumor-infiltrating lymphocytes for patients with completely resected stage IIIA(N2) non-small cell lung cancer.

BackgroundThe patient prognosis after complete resection for pathologic stage IIIA(N2) non-small cell lung cancer (NSCLC) remains a significant concern. The clinical relevance of the host immune response to NSCLC has yet to be established. We aimed to investigate the prognostic value of tumor-infiltrating lymphocytes (TILs) in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC.MethodsFrom 2005 to 2012, consecutive patients with pathologic stage IIIA(N2) NSCLC who underwent complete resection at our institution were reviewed. For each case, full-face hematoxylin and eosin-stained sections from surgical specimens were evaluated for the TIL density. A published, recommended TIL scoring scale was followed. The patients were stratified into the TIL− or TIL+ group based on pathologic evaluation.ResultsData from 320 patients were included in the analysis. Based on a median follow-up duration of 30.8 months, a higher density of TILs was associated with an improved postoperative survival time (P = 0.06). Subgroup analyses indicated that this positive effect was the greatest for patients with squamous cell carcinoma (SCC; P = 0.03). Among those with SCC, the TIL+ patients experienced a significantly increased 3-year distant metastasis-free survival (DMFS) compared to the TIL− patients (60.6% versus 42.7%, P = 0.02). Multivariate analyses of the 93 patients with SCC tumors confirmed that TIL+ was an independent prognostic factor for an increased DMFS (HR = 0.39, 95%CI 0.17–0.87, P = 0.02) and a prolonged overall survival (OS; HR = 0.47, 95%CI 0.22–1.00, P = 0.05).ConclusionsOur data suggest a potential role of TILs in predicting the survival of patients with completely resected stage IIIA(N2) NSCLC. The beneficial effects of TILs were more pronounced in the prediction of the DMFS and the OS in patients with SCC. This parameter should be considered for prospective inclusion in clinical trials.

Size matters: Survival benefit conferred by intratumoral T cells is dependent on surgical outcome, treatment sequence and T cell differentiation

ABSTRACTOutcome of cytoreductive surgery, treatment sequence and the differentiation status of T cells are key factors to take into account when studying the prognostic value of tumor-infiltrating lymphocytes (TIL) in high grade serous ovarian cancer.

Tumour-infiltrating lymphocyte scores effectively stratify outcomes over and above p16 post chemo-radiotherapy in anal cancer.

Background:The majority (90%) of anal cancers are human papillomavirus (HPV)-driven, identified using immunochemistry for p16. Compared with HPV− patients, those with HPV+ disease generally show improved survival, although relapse rates around 25% indicate a need for further stratification of this group.Methods:Using two cohorts of anal cancer, previously characterised for p16, we assessed the prognostic value of tumour-infiltrating lymphocytes (TILs).Results:Tumour-infiltrating lymphocyte scores were used to stratify p16+ cases, where tumours with absent/low levels of TIL had a relapse-free rate of 63%, as opposed to 92% with high levels of TIL (log rank P=0.006).Conclusions:Assessment of TIL adds to p16 status in the prognosis of anal cancer following chemo-radiotherapy and provides evidence of the clinical importance of the immune response.

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

The adaptive immune system is a crucial component of cancer immunoediting and has emerged, in recent years, as a key foundation on which the success of novel cancer therapeutics have been built, namely the checkpoint inhibitors. Early observational studies have highlighted the importance of tumor-infiltrating lymphocytes (TILs) in patient outcomes across multiple solid tumor types, reflecting its role in cancer immunosurveillance. High TILs in triple-negative breast cancer (TNBC), a poor prognostic subgroup, has been shown to be associated with improved survival. When evaluated in functional TIL subsets, a positive correlation has also been observed with cytotoxic CD8+ TILs but results were conflicting for FOXP3 regulatory T cells. Overexpression of immune response genes corresponded to increased lymphocytic infiltration and improved outcomes in TNBC. Understanding the functional biology of TILs and its interaction with cancer in the immunoediting processes will help guide immunotherapeutic approaches in TNBC.

Emerging Predictive Biomarkers of Response to Platinum Therapy in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a heterogeneous disease with different biological characteristics and treatment outcomes compared to other subtypes of breast cancer. Recently, platinum-based chemotherapy has received increased attention in TNBCs based on promising results especially in the neoadjuvant setting. Homologous recombination deficiency (HRD) and tumor infiltrating lymphocytes (TILs) are new emerging biomarkers associated with platinum efficacy. Despite heterogeneity of methods used for HRD assessment, results of published studies showed consistently the predictive value of HRD for efficacy of platinum-based chemotherapy, especially in the neoadjuvant setting. Prognostic value of TILs in TNBCs is consistent across the trials and while the predictive value of TILs for platinum-based therapy in TNBCs is promising, it needs to be confirmed in further trials. Further research should focus on prospective validation of these biomarkers to confirm their clinical utility, while combination of these markers could lead to composite biomarkers that mirror both tumor and microenvironment properties.

Predictive and prognostic value of tumor-infiltrating lymphocytes in breast cancer treated with neoadjuvant chemotherapy.

128 Background: The prognostic importance of tumor-infiltrating lymphocytes (TILs) in triple-negative (TN) and HER2-positive breast cancer has been suggested in recent trials. The aim of this study is to evaluate a relationship between TILs and response to neoadjuvant chemotherapy (NAC) as well as long-term outcome in breast cancer including luminal, TN and HER2 subtypes. Methods: Twenty-seven patients receiving NAC from January 2010 to March 2015 at Inagi Municipal Hospital were analyzed. Intratumoral lymphocytes (ItuLy) and stromal lymphocytes (StrLy) were evaluated in hematoxylin and eosin-stained sections from pretherapeutic core needle biopsies. Lymphocyte-predominant breast cancer (LPBC) was defined as tumors with &gt; 50% of ItuLy or StrLy. Results: A total of 27 patients were divided into 13 luminal (48.1%), 3 TN (11.1%) and 11 HER2 (40.7%) subtypes. The median age was 58 years and the median tumor size was 3.0 cm. A significant correlation between ItuLy (the median percentage: 5%) and StrLy (25%) was observed (Pearson correlation coefficient = 0.628, P&lt; 0.01). LPBC comprised 29.6% (8/27) of total population, with higher frequencies of 33.3% and 54.5% in the TN and HER2-positive subtypes, when compared with 7.7% in luminal subtype (P= 0.044). LPBC group had a significantly higher pathological complete response (pCR) rate of 62.5% (5/8), compared with 5.3% (1/19) for non-LPBC group (P= 0.004). LPBC showed the modest correlation with pCR in luminal (100% (1/1) vs. 0% (0/12), P= 0.077) and HER2-positive subtypes (66.6% (4/6) vs. 25% (1/5), P= 0.175). In TN subtype, neither LPBC nor non-LPBC showed pCR. After a median follow-up of 24.3 months, patients with any TILs were significantly associated with better disease-free survival (DFS) than those without TILs (24.3 vs. 23.6 months, P= 0.016). The most significant impact of TILs on DFS was observed in HER2-positive subtype (23.2 vs. 15.2 months, P= 0.046), whereas TILs did not associate with DFS in luminal and TN subtypes. Conclusions: The presence of TILs was a significant predictor for response to NAC and would provide useful information of prognosis in breast cancer.

Roles of Tumor-infiltrating Lymphocytes in Non-small Cell Lung Cancer Recurrence and Metastasis:A Meta Analysis

To determine the prognostic value of tumor-infiltrating lymphocytes in the recurrence and metastasis of non-small cell lung cancer (NSCLC). A PubMed, EMBASE, Cochrane Library databases, NIH databases, and China Biology Medicine disc, China National Knowledge Infrastructure, Chinese Science and Technology Periodical literature search strategy was designed. Studies on the prognostic values of intratumoural CD3⁺,CD4⁺,CD8⁺, and FoxP3+lymphocytes for NSLCL were retrieved. RevMan 5.1 was applied for Meta analysis. Totally 8 studies entered the final analysis. In pooled analysis of 1197 patients,the high expressions of CD3⁺ and CD8⁺ cells were correlated with the increase of overall survival (OS) (OR=0.52,95% CI=0.40- 0.68, P<0.0001; OR=0.52,95% CI=0.34-0.79,P=0.002), and the high expression of CD8⁺ was significantly correlated with the increase of disease-free survival (DFS) (OR=0.68,95% CI=0.51-0.91,P=0.01). The CD4⁺ cell expression level was not significantly correlated with OS or DFS (P=0.14, P=0.73). The high expression of FoxP3⁺ cells did not favor the DFS(OR=1.78,95% CI=1.36-2.31; P<0.0001). The expression levels of CD3⁺, CD8⁺ and FoxP3⁺ in NSCLC microenviroment are related with the prognosis of NSCLC, while the role of CD4⁺ in the development of NSCLC warrants further investigations.

CD8+ tumour-infiltrating lymphocytes in relation to HPV status and clinical outcome in patients with head and neck cancer after postoperative chemoradiotherapy: A multicentre study of the German cancer consortium radiation oncology group (DKTK-ROG).

We examined the prognostic value of tumour-infiltrating lymphocytes (TILs) in patients with squamous cell carcinoma of the head and neck (SCCHN) after surgery and postoperative cisplatin-based chemoradiotherapy. FFPE-tissue originating from the surgery of 161 patients treated in 8 DKTK partner sites was immunohistochemically stained for CD3 and CD8. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of the HPV16-DNA/p16 status. After a median follow-up of 48 months (range: 4100 months), OS at 4 years was 46.5% for the entire cohort. In multivariate analysis, high CD8 expression was confirmed as an independent prognostic parameter for OS (p = 0.002), LPFS (p = 0.004) and DMFS (p = 0.006), while CD3 expression lacked significance. In multivariate analysis HPV16 DNA positivity was associated with improved OS (p = 0.025) and LPFS (p = 0.013) and p16-positive patients showed improved DMFS (p = 0.008). Interestingly, high CD8 expression was a prognostic parameter for the clinical outcome in both HPV16 DNA-positive and HPV16 DNA-negative patients. Similar findings were observed in the multivariate analysis for the combined HPV16 DNA/p16 status. Altogether, CD8+ TILs constitute an independent prognostic marker in SCCHN patients treated with adjuvant chemoradiotherapy. These data indicate that CD8-positive TILs have antitumour activity and could be used for treatment stratification. Further validation of the prognostic value of CD8+ TILs as a biomarker and its role in the immune response in SCCHN patients after adjuvant chemoradiotherapy is warranted and will be performed in the prospective DKTK-ROG study.

Prognostic value of tumor-infiltrating lymphocytes (TILs) and expression of PD-L1 in cholangiocarcinoma.

294 Background: Cholangiocarcinoma is a malignancy arising from the epithelial cells of the biliary tract with poor prognosis. Tumor-infiltrating lymphocytes (TILs) have a prognostic impact in various solid tumors. We aimed to investigate TIL expression and programmed cell death ligand PD-L1 and their clinical relevance in cholangiocarcinoma. Methods: Formalin-fixed paraffin-embedded tumor samples from thirty seven patients with resected and histologically verified cholangiocarcinoma between 1990 and 2011 were identified and immunohistochemically (IHC) stained with anti CD8, anti CD45RO and the anti-PDL1 mouseIgG1 (clone 5H1; Thompson) antibodies on a Leica automated IHC platform. The stains were semiquantitatively analyzed using the AllRed score system (range 1 to 8). Cases with IHC score &gt; 3 were considered positive. The association between PDL1, CD45R0, overall survival (OS) and progressive free survival (PFS) was investigated using Kaplan-Meier survival and COX proportional hazard regression analyses. Results: The median age of patients was 64 (41-85) with 51% male. 25%, 59%, 10% and 5% were stage I, II, III, and IV respectively. CD8 was positive in 10/37 (27%) with median IHC of 5, CD45R0 (specimen with lymph node like structure) was positive in 16/37 (43%) with median IHC score of 4, PD-L1 was positive in 35/37 (94 %) with median IHC score of 8. Pts with tumors exhibiting lymph node (LN) like structures (CD45RO+) has better median OS (63 months vs 18 months, P = 0.0065) and median PFS (29 months vs 14.6 months, P = 0.05) than patients lacking LN like structures (CD45RO-). 5 yrs. OS in CD45RO+ was 64% vs 20% in CD45RO- (P 0.006) whereas 5 yrs. PFS in CD45RO+ was 41% vs. 8% in in CD45RO- pts (P value 0.05). Correlating PDL1 with OS and PFS was not done due to high expression of PD-L1 in most of the samples (94%). Conclusions: Presence of lymph node like structures (CD45RO+) was associated with significant better outcome reflecting the immune-mediated killing of tumor cells. The high expression of PD-L1 on cholangiocarcinoma cells represents a potential therapeutic target which may improve the prognosis for this dismal cancer. Future trials involving PD-L1 inhibitors in cholangiocarcinoma are warranted.

The prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancer: a meta-analysis.

In a recent meta-analysis, we demonstrated that rich tumor-infiltrating lymphocytes (TILs) were significantly correlated to a favorable breast cancer (BC) outcome largely in estrogen receptor-negative tumors. It is known that TILs predominate in triple-negative (TN) BC, and to the best of our knowledge, there is no published meta-analysis that examined their prognostic value exclusively in that subtype. Therefore, we planned this meta-analysis to explore the clinical utility of rich TILs in TN-BC. According to predefined selection criteria, literature search identified eight eligible studies. The meta-analysis included data on 2,987 patients with early stage BC. The median percentage of lymph node positivity was 47% (95% confidence interval [CI] 23-82%). Over a median follow-up of 113 months (95% CI 80-144 months), it was found that rich TILs were associated with 30% (hazard ratio [HR] = 0.70; 95% CI 0.56-0.87; P = 0.001), 22% (HR = 0.78; 95% CI 0.68-0.90; P = 0.0008), and 34% (HR = 0.66; 95% CI 0.53-0.83; P = 0.0003), reduction in the risk of recurrence, distant recurrence, and death, respectively. In addition, for every 10% increments in rich TILs, there was an approximate 15-20% reduction in any recurrence, distant recurrence, or mortality. Moreover, rich TILs predicted superior overall survival (OS) benefit irrespective of the disease phenotype (TN-BC or core-basal phenotype), TILs location (intratumoral or stromal), or TILs qualification as either TILs-non-specified, cytotoxic (CD8+) or regulatory (forkhead box protein 3, FOXP3+) T cells. Data on 5-negative phenotype population were limited, and rich TILs failed to demonstrate a prognostic significance in this phenotype. To investigate the heterogeneity that was shown in the analyses of disease-free survival and OS, a set of meta-analyses showed that the method used in TILs detection (hematoxylin and eosin stains vs. immunohistochemistry) could explain most of the variability in the pooled estimates. Rich TILs were significantly associated with better survival outcome in early TN-BC and should be considered as a strong prognostic factor in this subtype. The results from the current meta-analysis support integrating immunotherapy with conventional therapy in future BC research.

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.

Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.