Value Of Tumor-infiltrating Immune Cells Research Articles

Gastric cancer immune microenvironment score predicts neoadjuvant chemotherapy efficacy and prognosis.

The efficacy of neoadjuvant chemotherapy (NACT) in patients with advanced gastric cancer (GC) varies greatly. Thus, we aimed to verify the predictive value of tumor-infiltrating immune cells (TIICs) on the treatment response to NACT and the prognosis of patients with advanced GC, and to explore the impact of NACT on the tumor immune microenvironment (TIME). Paired tumor tissues (pre- and post-NACT) from patients with advanced GC were collected for this study. TIICs were assessed using immunohistochemistry staining and analyzed using logistic regression to establish an immune microenvironment score for GC (ISGC score) and predict NACT efficacy. Kaplan-Meier curves were used to evaluate the survival outcome of patients. The results showed that TIME was dramatically heterogeneous between NACT response and nonresponse patients. In the validation cohort, the ISGC score demonstrated good predictive performance for treatment response to NACT. Moreover, high ISGC indicated better long-term survival in patients with advanced GC. Furthermore, tumor-infiltrated T cells (CD3+ and CD8+) and CD11c+ macrophages were significantly increased in the response group, while CD163+ macrophages and FOXP3+ Treg cells were decreased after NACT. However, opposite results were exhibited in the nonresponse group. Finally, we found that the percentage of programmed cell death ligand 1 (PD-L1)-positive tumors was 31% (32/104) pre-NACT and 49% (51/104) post-NACT, and almost all patients with elevated PD-L1 were in the NACT response group. The ISGC model accurately predicted NACT efficacy and classified patients with GC into different survival groups. NACT regulates the TIME in GC, which may provide strategies for personalized immunotherapy.

An Activated Dendritic-Cell-Related Gene Signature Indicative of Disease Prognosis and Chemotherapy and Immunotherapy Response in Colon Cancer Patients

Accumulating evidence has underscored the prognostic value of tumor-infiltrating immune cells in the tumor microenvironment of colon cancer (CC). In this retrospective study, based on publicly available transcriptome profiles and clinical data from the Gene Expression Omnibus and The Cancer Genome Atlas databases, we derived and verified an activated dendritic cell (aDC)-related gene signature (aDCRS) for predicting the survival outcomes and chemotherapy and immunotherapy response of CC patients. We quantified the infiltration abundance of 22 immune cell subtypes via the “CIBERSORT” R script. Univariate Cox proportional hazards (PHs) regression was used to identify aDC as the most robust protective cell type for CC prognosis. After selecting differentially expressed genes (DEGs) significantly correlated with aDC infiltration, we performed univariate Cox-PH regression, LASSO regression, and stepwise multivariate Cox-PH regression successively to screen out prognosis-related genes from selected DEGs for constructing the aDCRS. Receiver operating characteristic (ROC) curves and Kaplan–Meier (KM) analysis were employed to assess the discriminatory ability and risk-stratification capacity. The “oncoPredict” package, Cancer Treatment Response gene signature DataBase, and Tumor Immune Dysfunction and Exclusion algorithm were utilized to estimate the practicability of the aDCRS in predicting response to chemotherapy and immune checkpoint blockade. Gene set enrichment analysis and single-cell RNA sequencing analysis were also implemented. Furthermore, an aDCRS-based nomogram was constructed and validated via ROC curves, calibration plots and decision curve analysis. In conclusion, aDCRS and an aDCRS-based nomogram will facilitate precise prognosis prediction and individualized therapeutic interventions, thus improving the survival outcomes of CC patients in the future.

Relationship between Tumor Infiltrating Immune Cells and Tumor Metastasis and Its Prognostic Value in Cancer.

Tumor metastasis is an important reason for the difficulty of tumor treatment. Besides the tumor cells themselves, the tumor microenvironment plays an important role in the process of tumor metastasis. Tumor infiltrating immune cells (TIICs) are one of the main components of TME and plays an important role in every link of tumor metastasis. This article mainly reviews the role of tumor-infiltrating immune cells in epithelial mesenchymal transformation, extracellular matrix remodeling, tumor angiogenesis and formation of pre-metastatic niche. The value of TIICs in the prognosis of cervical cancer, lung cancer and breast cancer was also discussed. We believe that accurate prognosis of cancer treatment outcomes is conducive to further improving treatment regimens, determining personalized treatment strategies, and ultimately achieving successful cancer treatment. This paper elucidates the relationship between tumor and TIICs in order to explore the function of immune cells in different diseases and provide new ideas for the treatment of cancer.

Differentially Infiltrated Identification of Novel Diagnostic Biomarkers Associated with Immune Infiltration in Nasopharyngeal Carcinoma.

The prognostic value of tumor-infiltrating immune cells has been widely studied in nasopharyngeal carcinoma (NPC). However, the role of tumor-infiltrating immune cells in the diagnosis of NPC has not been fully elucidated. Thus, tumor-infiltrating immune cell-related biomarkers in the diagnosis of NPC patients were explored in the current study. Gene expression profiles of NPC patients were downloaded from the Gene Expression Omnibus (GEO) database. Differentially infiltrating immune cells (DDICs) between NPC and control samples were analyzed by the CIBERSORT algorithm. Weighted gene coexpression network analysis (WGCNA) was performed to screen hub genes significantly correlated with DDIC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of hub genes were performed with R package clusterProfiler. The diagnostic value of hub genes was evaluated by receiver operating characteristic (ROC) curves. RT-qPCR was conducted to validate the expression patterns of diagnostic markers in NPC and adjacent control tissues. The correlations between diagnostic markers and immunomodulators were analyzed using the TISIDB. The protein-protein interaction (PPI) network based on immunomodulators significantly associated with diagnostic biomarkers was constructed and visualized by STRING. The functional enrichment analysis of genes in the PPI network was analyzed by the WebGestalt online tool. The abundances of memory B cells, plasma cells, follicular helper T cells, activated NK cells, M0 macrophages, M1 macrophages, M2 macrophages, resting mast cells, and activated mast cells were significantly different between NPC and control samples. Dark orange was identified as the hub module, with a total of 371 genes associated with memory B cells, plasma cells, and M0 and M1 macrophages defined as hub genes, which were enriched into immune-related biological processes and pathways. FCER2, KHDRBS2, and IGSF9 were considered diagnostic biomarkers with areas under ROC curves as 0.985, 0.978, and 0.975, respectively. Moreover, real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) suggested that the expression patterns of FCER2, KHDRBS2, and IGSF9 were consistent with the results in GEO datasets. TISIDB analysis revealed that FCER2, KHDRBS2, and IGSF9 had a strong association with 8 immunoinhibitors (BTLA, CD160, CD96, LAG3, PDCD1, TIGIT, CD244, and TGFB1) and 11 immunostimulators (CD27, CD28, CD40LG, CD48, ICOS, KLRC1, KLRK1, TMIGD2, TNFRSF13C, CXCR4, and C10 or f54). The PPI network implied that these 19 immunomodulators had interactions with other 50 genes. WebGestalt analysis demonstrated that 69 genes in the PPI network were enriched into cytokine-cytokine receptor interaction, NF-kappa B signaling pathway, and pathways in cancer. Our study identified novel diagnostic biomarkers and revealed potential immune-related mechanisms in NPC. These findings enlighten the investigation of the molecular mechanisms of tumor-infiltrating immune cells regulating NPC.

Prognostic value of tumor-infiltrating immune cells and immune checkpoints in elderly head-and-neck squamous cell carcinoma patients undergoing definitive (chemo)radiotherapy

Background and purposeTumor-infiltrating lymphocytes (TILs) are associated with locoregional control (LRC) in head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiotherapy. As immunosenescence results in reduced immune activity, the role of TILs in elderly HNSCC patients may differ compared to younger patients, providing a rationale to study the prognostic role of TILs and immune checkpoints (ICs) in this population.Material and methodsSixty-three HNSCC patients aged ≥ 65 years undergoing definitive (chemo)radiotherapy between 2010 and 2019 with sufficient material from pre-treatment biopsies were included in the analysis. Immunohistochemical stainings of CD3, CD4, CD8, PD-L1, TIM3, LAG3, TIGIT and CD96, and of osteopontin as an immunosenescence-associated protein were performed. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan–Meier method, and Fine-Gray's models were used for locoregional failure (LRF) analyses.ResultsWhile there was no correlation between patient age and IC expression, osteopontin levels correlated with increasing age (r = 0.322, p < 0.05). Two-year OS, PFS, and LRC were 44%, 34%, and 71%, respectively. Increased LAG3 expression, both intraepithelial (SHR = 0.33, p < 0.05) and stromal (SHR = 0.38, p < 0.05), and elevated stromal TIM3 expression (SHR = 0.32, p < 0.05) corresponded with reduced LRFs. Absent tumoral PD-L1 expression (TPS = 0%) was associated with more LRFs (SHR = 0.28, p < 0.05). There was a trend towards improved LRF rates in elderly patients with increased intraepithelial CD3 + (SHR = 0.52, p = 0.07) and CD8 + (SHR = 0.52, p = 0.09) TIL levels.ConclusionLAG3, TIM3 and TPS are promising biomarkers in elderly HNSCC patients receiving (chemo)radiotherapy. Considering the frequency of non-cancer related deaths in this population, the prognostic value of these biomarkers primarily relates to LRC.

Prognostic value of tumor-infiltrating immune cells in clinical early-stage oral squamous cell carcinoma.

Tumor-infiltrating immune cells (TIICs) are critical components of tumor immune microenvironment (TIME), which play crucial roles during tumor initiation, development, and progression. However, the prognostic value of TIICs is still not well documented in clinical early-stage oral squamous cell carcinoma (OSCC). In this study, we aimed to assess the prognostic value of TIICs in clinical early-stage OSCC and develop a nomogram based on TIICs to predict the prognosis. Eighty patients with clinical early-stage (cT1,2N0M0) OSCC were enrolled in this study. Immunohistochemical staining was performed to evaluate the infiltration of TIICs, including CD8+ T cells, CD57+ NK cells, CD163+ macrophage, and CD20+ B cells. Overall survival (OS) and disease-free survival (DFS) curves were plotted by the Kaplan-Meier method. Cox's proportional hazards regression models were performed to assess the prognostic value of TIICs. Finally, a nomogram was established to predict the OS based on TIICs infiltration and assessed by concordance index (C-index) and calibration curve. High infiltrations of CD57+ NK cells and CD20+ B cells indicated a better OS in clinical early-stage OSCC. Moreover, high infiltration of CD20+ B cells favored a longer DFS. Of note, low infiltrations of CD57+ NK cells and CD20+ B cells were independent prognostic factors for poor OS in clinical early-stage OSCC. The nomogram that combined CD57+ NK cells with CD20+ B cells could predict the OS in clinical early-stage OSCC, and the C-index was 0.801 (95% CI: 0.679-0.924). The calibration plot showed that prediction and observation are well matched. High infiltration of CD57+ NK cells and CD20+ B cells indicate a favorable OS in clinical early-stage OSCC. The nomogram constructed based on TIICs might be used for predicting the prognosis in clinical early-stage OSCC.

Potential Prognosis and Diagnostic Value of AKT3, LSM12, MEF2C, and RAB30 in Exosomes in Colorectal Cancer on Spark Framework.

Colorectal cancer (CRC) is a common malignant tumor and one of the leading causes of cancer-related deaths worldwide. CRC progression is greatly affected by the local microenvironment. In the study, we proposed a deep computational-based model for the classification of mRNA, lncRNA, and circRNA in exosomes. We, first, analyzed mRNA expression levels in CRC tumors and normal tissues. Secondly, we used GO and KEGG to analyze their functional enrichment. Thirdly, we analyzed the composition of immune cells in all TCGA samples and then evaluated the prognostic value of tumor-infiltrating immune cells in CRC. Lastly, we combined the TCGA dataset, i.e., COADN = 449 and ROADN = 6, for analysis and found that the expression levels of AKT3, LSM12, MEF2C, and RAB30 in exosomes were significantly correlated with tumor immune infiltration levels. The performance evaluation has shown that the proposed model based on neural networks performs better as compared to the existing methods. The proposed model can be used as a potential tool for the immune infiltration level and their role in cancer metastasis and progression, which can help us to explore potential strategies for CRC diagnosis, therapy, and prognosis.

The prognostic landscape of tumor-infiltrating immune cells in lung squamous cell carcinoma.

BackgroundExploring novel biomarkers and developing effective therapeutic strategies can improve the prognosis of lung squamous cell carcinoma (LUSC) in the future. The prognostic value of tumor-infiltrating immune cells (TICs) in solid tumors has been extensively studied. However, the landscape of TICs involved in the prognosis of non-small cell lung cancer (NSCLC), especially in LUSC, remains unclear and should be systematically investigated.MethodsThis retrospective study analyzed the immune-related transcriptional profiles of 490 LUSC patients from The Cancer Genome Atlas (TCGA) cohort. Using the CIBERSORT method, TICs were evaluated and examined for their association with overall survival (OS) in LUSC.ResultsOut of the 27 TICs, 14 were correlated with prognosis in LUSC. A novel prognostic model characterized by fewer memory B cells and more central memory CD8 T cells, regulatory T cells (Tregs), and plasmacytoid dendritic cell (pDC) infiltration predicted poor OS in LUSC with high accuracy. The 1-, 3-, and 5-year areas under the curve (AUC) were 0.95, 0.98, and 0.96, respectively, in the training cohort. This finding was further validated in the validation cohort, where the 1-, 3-, and 5-year AUCs were 0.95, 0.98, and 0.95, respectively.ConclusionsThese findings may provide more effective prognostic biomarkers and potential therapeutic targets for the immunotherapy of LUSC.

Abstract PS5-27: The predictive value of tumor-infiltrating lymphocytes and PD-L1 expression on the efficacy of neoadjuvant trastuzumab plus chemotherapy in HER2-positive breast cancer

Abstract Background:Many studies have explored the predictive factors for the efficacy of neoadjuvant therapy in HER2 + breast cancer. However, no reliable and widely used biomarker was found till now except several clinicalpathologic factors including HER2. HER2 oncogene can regulate the recruitment and activation of tumor-infiltrating immune cells (TILs) and trastuzumab therapeutic effects by inducing programmed death ligand 1 (PD-L1), suggesting that TILs and the expression of PD-L1 may be associated with the efficacy of trastuzumab. Several studies have verified certain predictive value of TILs and PD-L1 in HER2 + breast cancer patients, but controversy remains. Besides, most of them focus on the expression of PD-L1 or TILs before neoadjuvant therapy, but not the change in the paired tissues before and after neoadjuvant therapy. This study aimed to investigate the change of TILs and the expression of PD-L1 in the paired tissues before and after neoadjuvant therapy and the correlation to the efficacy of neoadjuvant trastuzumab plus chemotherapy and disease-free survival (DFS) in HER2+ breast cancer patients.Methods:HER2+ breast cancer cases receiving neoadjuvant therapy (n=115) were retrospectively collected between July 2013 and November 2018. The expression of PD-L1 was detected by immunohistochemistry using SP142 antibody and the percentage of positive membranous staining in tumor cells (TC-PD-L1) and TILs (TILs-PD-L1) was scored respectively. TIL percentile score for full sections were assessed by two pathologists independently. Results:In our study, 87 patients receiving neoadjuvant chemotherapy alone, and 68 patients receiving neoadjuvant trastuzumab plus chemotherapy. Among them, 39 patients achieved pCR and 116 patients were non-pCR. Univariate analysis confirmed that the pCR was positively correlated with high TILs and TILs-PD-L1 expression before neoadjuvant therapy (P&amp;lt; 0.05). Multivariate logistic regression analysis confirmed that pre-treatment TILs-PD-L1 expression but no other clinicalpathologic factors,was independent predictor of pCR in neoadjuvant therapy (P&amp;lt;0.05).Among all patients, TILs increased in breast cancer tissues after neoadjuvant therapy (P&amp;lt;0.001). Consistent results were found in subgroup analysis of trastuzumab plus chemotherapy group and chemotherapy alone group (P&amp;lt;0.05). In 116 non-pCR patients, TC-PD-L1 was down-regulated in breast cancer tissues after neoadjuvant therapy (P=0.0219). Consistent results were found in 43 non-pCR patients receiving neoadjuvant trastuzumab plus chemotherapy(P=0.0437). While in 73 non-pCR patients receiving neoadjuvant chemotherapy, there was no significant difference in TC-PD-L1 expression before and after neoadjuvant therapy (P=0.1465). On the other hand, in the general population, neoadjuvant trastuzumab plus chemotherapy group and neoadjuvant chemotherapy group, TILs-PD-L1 were all down-regulated after treatment(P&amp;lt;0.05).Kaplan-Meier analysis showed that the changes of TILs, TC-PD-L1, TILs-PD-L1 between pre and post neoadjuvant therapy have no correlations with DFS. In multivariate Cox regression analysis, lymph node status and distant metastasis were independent prognostic factors for DFS.Conclusions:1. Pre-treatment high TILs-PD-L1 was an independent predictor of PCR in patients with HER2+ breast cancer treated with neoadjuvant therapy.2. Trastuzumab maybe relate to the down-regulation of TC-PD-L1 and TILs-PD-L1 expression. 3. Lymph node status and distant metastasis were independent prognostic factors.4. Both TILs-PD-L1 and TILs change before and after neoadjuvant therapy for HER2-positive breast cancer, which may suggest that the immune microenvironment plays a role in neoadjuvant therapy. Citation Format: Huihui Li, Mao Shang, Yajing Chi, Sha Yin. The predictive value of tumor-infiltrating lymphocytes and PD-L1 expression on the efficacy of neoadjuvant trastuzumab plus chemotherapy in HER2-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-27.

Density of CD3+ and CD8+ cells in gingivo-buccal oral squamous cell carcinoma is associated with lymph node metastases and survival.

The tumor immune microenvironment is emerging as a critical player in predicting cancer prognosis and response to therapies. However, the prognostic value of tumor-infiltrating immune cells in Gingivo-Buccal Oral Squamous Cell Carcinoma (GBOSCC) and their association with tumor size or lymph node metastases status require further elucidation. To study the relationship of tumor-infiltrating immune cells with tumor size (T stage) and lymph node metastases (N stages), we analyzed the density of tumor-infiltrating immune cells in archived, whole tumor resections from 94 patients. We characterized these sections by immune-histochemistry using 12 markers and enumerated tumor-infiltrating immune cells at the invasive margins (IM) and centers of tumors (CT). We observed that a higher density of CD3+ cells in the IM and CT was associated with smaller tumor size (T1-T2 stage). Fewer CD3+ cells was associated with larger tumor size (T3-T4 stage). High infiltration of CD3+and CD8+ cells in IM and CT as well as high CD4+ cell infiltrates in the IM was significantly associated with the absence of lymph node metastases. High infiltrates of CD3+ and CD8+ cells in CT was associated with significantly improved survival. Our results illustrate that the densities and spatial distribution of CD3+ and CD8+ cell infiltrates in primary GBOSCC tumors is predictive of disease progression and survival. Based on our findings, we recommend incorporating immune cell quantification in the TNM classification and routine histopathology reporting of GBOSCC. Immune cell quantification in CT and IM may help predict the efficacy of future therapies.

Prognostic and Predictive Value of Tumor-Infiltrating Immune Cells in Urothelial Cancer of the Bladder.

Simple SummaryThere is substantial heterogeneity in the prognosis and responsiveness to registered therapies in bladder cancer. Biomarkers that can accurately predict prognosis and treatment outcome are urgently needed. Bladder cancer is considered an immunogenic tumor. In this review, we describe the available literature on the prognostic and predictive value of tumor-infiltrating immune cells and immune checkpoint expression. Several immunological markers have been associated with prognosis and treatment outcome. These markers have not yet been implemented in the clinic, likely due to the limited prognostic or predictive value of the individual markers. Future studies should, therefore, focus on combinations of biomarkers to accurately predict survival and response to treatment. The extensive overview provided here can be used to guide further biomarker research in bladder cancer. The prognosis and responsiveness to chemotherapy and checkpoint inhibitors differs substantially among patients with bladder cancer (BC). There is an unmet need for biomarkers that can accurately predict prognosis and treatment outcome. Here, we describe the available literature on the prognostic and predictive value of tumor-infiltrating immune cells in BC. Current evidence indicates that a high density of tumor-infiltrating CD8+ T cells is a favorable prognostic factor, whereas PD-L1 expression and tumor-associated macrophages are unfavorable prognostic features. While PD-L1 expression appears unsuccessful as a biomarker for the response to checkpoint inhibitors, there are some indications that high CD8+ T cell infiltration, low transforming growth factor-beta signaling and low densities of myeloid-derived suppressor cells are associated with response. Future studies should focus on combinations of biomarkers to accurately predict survival and response to treatment.

The landscape and prognostic value of tumor-infiltrating immune cells in gastric cancer.

BackgroundGastric cancer (GC) is the fourth most frequently diagnosed malignancy and the second leading cause of cancer-associated mortality worldwide. The tumor microenvironment, especially tumor-infiltrating immune cells (TIICs), exhibits crucial roles both in promoting and inhibiting cancer growth. The aim of the present study was to evaluate the landscape of TIICs and develop a prognostic nomogram in GC.Materials and MethodsA gene expression profile obtained from a dataset from The Cancer Genome Atlas (TCGA) was used to quantify the proportion of 22 TIICs in GC by the CIBERSORT algorithm. LASSO regression analysis and multivariate Cox regression were applied to select the best survival-related TIICs and develop an immunoscore formula. Based on the immunoscore and clinical information, a prognostic nomogram was built, and the predictive accuracy of it was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve (ROC) and the calibration plot. Furthermore, the nomogram was validated by data from the International Cancer Genome Consortium (ICGC) dataset.ResultsIn the GC samples, macrophages (25.3%), resting memory CD4 T cells (16.2%) and CD8 T cells (9.7%) were the most abundant among 22 TIICs. Seven TIICs were filtered out and used to develop an immunoscore formula. The AUC of the prognostic nomogram in the TCGA set was 0.772, similar to that in the ICGC set (0.730) and whole set (0.748), and significantly superior to that of TNM staging alone (0.591). The calibration plot demonstrated an outstanding consistency between the prediction and actual observation. Survival analysis revealed that patients with GC in the high-immunoscore group exhibited a poor clinical outcome. The result of multivariate analysis revealed that the immunoscore was an independent prognostic factor.DiscussionThe immunoscore could be used to reinforce the clinical outcome prediction ability of the TNM staging system and provide a convenient tool for risk assessment and treatment selection for patients with GC.

The prognostic landscape of tumor-infiltrating immune cells in cervical cancer

Tumor-infiltrating immune cells (TICs) are highly relevant to tumor development and are promising prognostic biomarkers. However, the precise assessment of TICs is limited by the deficiencies of traditional measurements, such as the lack of phenotypic markers. Here, we analyzed the composition of TICs in cervical cancer based on RNA expression data with a metagene approach called CIBERSORT and evaluated the prognostic value of TICs. The immune infiltration profiles functioned as intrinsic features to distinguish cervical cancer from normal tissue. According to the Cox regression analysis, higher levels of activated memory CD4+ T cells were independently associated with favorable overall survival (OS) (hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.57–0.89; p = 0.003), whereas a higher fraction of activated mast cells was independently associated with adverse outcomes (HR = 1.53, 95% CI: 1.23–1.91; p < 0.001). Furthermore, a novel prognostic model named aTMNs (activated memory CD4+ T cells, activated mast cells and activated natural killer [NK] cells) was constructed to predict OS in cervical cancer with high accuracy (area under the curve [AUC] = 0.723, concordance index [C-index] = 0.738): risk score = −0.34508 × (proportion of activated memory CD4+ T cells) + 0.426841 × (proportion of activated mast cells) + 0.272202 × (proportion of activated NK cells). The aTMNs model outperformed the immunomodulator model (AUC = 0.673, C-index = 0.693). Overall, TICs are important prognostic determinants in cervical cancer and may be a useful resource for the development of effective immunotherapy.

Abstract 4144: The prognostic value of tumor-infiltrating immune cells and clinical application of immunoscoring methods in advanced colorectal carcinoma

Abstract Background Immunoscore(IS) which quantifies tumor-infiltrating lymphocyte (TIL) has been noteworthy for novel prognostic biomarker especially in colorectal cancer (CRC). Recent studies have been insisted that IS method is superior to current tumor-node-metastases staging system in various cancers. The prognostic significance of tumor-associate macrophage (TAM) also has been suggested. However, studies in the past included patients with stage I-III CRCs and the clinical implication of TIL and TAM has not been fully clarified in advance CRC patients who presented distant metastases. In this study, we investigated TIL and TAM in the primary site and the corresponding metastatic organ to identified the heterogeneity of each characteristics according to tumor location. We evaluated the prognostic significance of TIL and TAM in advanced CRCs. Also we designed new IS methods and conducted comparative analysis between existing and new methods for prognostic predictive value. Methods. Using immunohistochemistry and digital image analyzer, we measured the density of CD3, CD4, CD8 and FOXP3-positive lymphocyte of 196 advanced CRC patients. CD68 and CD163 immunohistochemistry was conducted to evaluate the density of tumor-associated macrophage. These properties were examined within tissue from four sites (the center (CT) and periphery of the primary cancer (IM), a distant metastasis (DM) and a lymph node metastasis (LM)). High density of lymphocyte marker and low density of macrophage marker in each region recorded as a score. IS method is based on the combination of two markers (CD3 and CD8) in two regions (CT and IM). Newly designed model, IS-metastatic and IS-macrophage included the additional scores of two markers (CD3 and CD8) in DM and macrophage markers (CD68 and CD163) in CT, respectively. Results. The each density of TIL and TAM showed significant heterogeneity according to the tumor location. Patients with high density of CD3-positive lymphocyte in CT presented favorable outcome (p = 0.030). In contrast, patients showing high density of CD68 and CD163-positive macrophage in CT had significantly worse prognosis (p = 0.011 and p&amp;lt;0.001, respectively). Higher IS (score 3-4) was significantly correlated with better survival rate (p = 0.020). Patients with higher IS-metastatic as well as IS-macrophage (score 4-6) also showed significantly better outcome (p = &amp;lt;0.001 and p = 0.005, respectively). In multivariate analysis, IS-Metastatic model was independent prognostic factor (p = 0.012). Conclusions. TIL and TAM are distributed heterogeneously with respect to the tumor location in CRC patients and has a significant effect on patients outcome. IS is reproducible methods and applicable for predicting survival in advanced CRC. New IS model including CD3- and CD8-positive cells at distant metastasis could be an independent prognostic biomarker in advanced CRC patients. Citation Format: Yoonjin Kwak, Duck Woo Kim, Sung Bum Kang, Woo Ho Kim, Hye Seung Lee. The prognostic value of tumor-infiltrating immune cells and clinical application of immunoscoring methods in advanced colorectal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4144.

Prognostic and predictive value of tumor-infiltrating immune cells in Japanese patients with stage II/III gastric cancer.

46 Background: Since the ACTS-GC trial, Japanese patients with stage II/III gastric cancer (GC) receive adjuvant S1 chemotherapy. However, selection of patients (pts) by TNM stage does not predict benefit from adjuvant S1 with certainty. Thus, there is an urgent clinical need to identify predictive biomarkers. Increasing evidence suggests tumor immune cell infiltration may be related to GC pts prognosis. We tested the hypothesis that extent and type of immune cell infiltration in GC is related to benefit from adjuvant chemotherapy. Methods: Tissue microarrays from 252 GC resections (109 pts treated by surgery alone (S), 143 pts treated by surgery and adjuvant S1 chemotherapy (SC)) from the Kanagawa Cancer Center Hospital (Yokohama, Japan) were investigated by immunohistochemistry for common leucocytes antigen (CD45), neutrophils (CD66b), macrophages (CD68 and CD163), T-cell subtypes (CD45R0, CD8, CD3), B-cells (CD20) and Treg cells (FOXP3). Staining was quantified as percentage immunoreactivity/area by automated image analysis. Relationship with overall survival was analyzed. A Cox regression model was used to identify independent prognostic markers and treatment interaction effect. Results: The hazard ratio of S1 was 0.694 in this GC cohort which is similar to the results of the ACTS-GC trial. CD45 and CD45R0 were independent prognostic markers in the S group only (CD45 p=0.032, CD45R0 p=0.003). A treatment interaction effect was seen for CD45, CD45R0, and CD68 (p value for test of interaction: CD45 p=0.062, CD45R0 p=0.082, CD68 p=0.057). Survival in the SC group was significantly poorer compared to the S group for CD45&gt;56% or CD68&gt;7% (p&lt;0.05). Conclusions: This is the first study to investigate the relationship between tumor immune cell infiltration at time of surgery and benefit from adjuvant chemotherapy. Our results indicate that GC patients with high intratumoral levels of CD68, CD45, or CD45R0 positive immune cells might not benefit from adjuvant S1 chemotherapy. These findings require validation in a second independent dataset before conducting a prospective study stratifying patients with stage II/III GC based upon extent of CD45, CD45R0, or CD68 immune cell infiltration for adjuvant treatment.

Prognostic value of tumor-infiltrating immune cells in melanoma

Host cells representing an integral component of solid tumors, among them cells contributing to the development of native and adaptive immune responses, can exert both positive and negative effects on the outcome of the disease. Infiltration of T lymphocyte subsets and antigen presenting dendritic cells, crucial in mounting an efficient antitumor immune response, is generally associated with favorable prognosis. On the contrary, accumulation of tumor-associated macrophages, mast cells and neutrophils, playing important roles in chronic inflammatory processes promoting tumor progression, predicts unfavorable disease outcome in most cases. In melanoma, studies on the prognostic impact of the lymphoid infiltrate in general, and that of T cells, yielded controversial results. In our studies, density of activated T lymphocytes correlated with patients' survival, and we obtained similar results in the case of B cells and mature dendritic cells. The amount of both B cells and dendritic cells showed correlation with that of activated T lymphocytes, and their combined analysis identified patient subgroups with different prognosis. According to data from the literature, intense infiltration by neutrophil granulocytes could be associated with shorter survival, while no unambiguous conclusions can be drawn from studies on the prognostic value of tumor-associated macrophages and other immune cell types. Our results indicate that a prominent infiltration of dendritic cells, B cells and activated T lymphocytes can be considered as a favorable prognostic factor in malignant melanoma.