Pan-cancer single-cell landscape of tumor-infiltrating T cells.

T cells play a central role in cancer immunotherapy, but we lack systematic comparison of the heterogeneity and dynamics of tumor-infiltrating T cells across cancer types. We built a single-cell RNA-sequencing pan-cancer atlas of T cells for 316 donors across 21 cancer types and revealed distinct T cell composition patterns. We found multiple state-transition paths in the exhaustion of CD8+ T cells and the preference of those paths among different tumor types. Certain T cell populations showed specific correlation with patient properties such as mutation burden, shedding light on the possible determinants of the tumor microenvironment. T cell compositions within tumors alone could classify cancer patients into groups with clinical trait specificity, providing new insights into T cell immunity and precision immunotherapy targeting T cells.

Single-Cell RNAseq Profiling of Human γδ T Lymphocytes in Virus-Related Cancers and COVID-19 Disease.

The detailed characterization of human γδ T lymphocyte differentiation at the single-cell transcriptomic (scRNAseq) level in tumors and patients with coronavirus disease 2019 (COVID-19) requires both a reference differentiation trajectory of γδ T cells and a robust mapping method for additional γδ T lymphocytes. Here, we incepted such a method to characterize thousands of γδ T lymphocytes from (n = 95) patients with cancer or adult and pediatric COVID-19 disease. We found that cancer patients with human papillomavirus-positive head and neck squamous cell carcinoma and Epstein-Barr virus-positive Hodgkin's lymphoma have γδ tumor-infiltrating T lymphocytes that are more prone to recirculate from the tumor and avoid exhaustion. In COVID-19, both TCRVγ9 and TCRVγnon9 subsets of γδ T lymphocytes relocalize from peripheral blood mononuclear cells (PBMC) to the infected lung tissue, where their advanced differentiation, tissue residency, and exhaustion reflect T cell activation. Although severe COVID-19 disease increases both recruitment and exhaustion of γδ T lymphocytes in infected lung lesions but not blood, the anti-IL6R therapy with Tocilizumab promotes γδ T lymphocyte differentiation in patients with COVID-19. PBMC from pediatric patients with acute COVID-19 disease display similar γδ T cell lymphopenia to that seen in adult patients. However, blood γδ T cells from children with the COVID-19-related multisystem inflammatory syndrome are not lymphodepleted, but they are differentiated as in healthy PBMC. These findings suggest that some virus-induced memory γδ T lymphocytes durably persist in the blood of adults and could subsequently infiltrate and recirculate in tumors.

Metavariables Resuming Host Immune Features and Nodal Involvement Are Associated with Oncological Outcomes in Oral Cavity Squamous Cell Carcinoma.

Oral cavity squamous cell carcinoma (OSCC) is a common head and neck cancer characterized by a poor prognosis associated with locoregional or distant failure. Among the predictors of prognosis, a dense infiltration of adaptive immune cells is protective and associated with improved clinical outcomes. However, few tools are available to integrate immune contexture variables into clinical settings. By using digital microscopy analysis of a large retrospective OSCC cohort (n = 182), we explored the clinical significance of tumor-infiltrating CD8+ T-cells. To this end, CD8+ T-cells counts were combined with well-established clinical variables and peripheral blood immune cell parameters. Through variable clustering, five metavariables (MV) were obtained and included descriptors of nodal (NODALMV) and primary tumor (TUMORMV) involvement, the frequency of myeloid (MYELOIDMV) or lymphoid (LYMPHOIDMV) peripheral blood immune cell populations, and the density of tumor-infiltrating CD8+ T-cells (TI-CD8MV). The clinical relevance of the MV was evaluated in the multivariable survival models. The NODALMV was significantly associated with all tested outcomes (p < 0.001), the LYMPHOIDMV showed a significant association with the overall, disease-specific and distant recurrence-free survival (p < 0.05) and the MYELOIDMV with the locoregional control only (p < 0.001). Finally, TI-CD8MV was associated with distant recurrence-free survival (p = 0.029). Notably, the performance in terms of survival prediction of the combined effect of NODALMV and immune metavariables (LYMPHOIDMV, MYELOIDMV and TI-CD8MV) was superior to the TNM stage for most of the outcomes analyzed. These findings indicate that the analysis of the baseline host immune features are promising tools to complement clinical features, in stratifying the risk of recurrences.

MK-6, a novel not-α IL-2, elicits a potent antitumor activity by improving the effector to regulatory T cell balance.

IL-2 is a pleiotropic cytokine that regulates immune cell homeostasis. Its immunomodulatory function has been used clinically as an active immunotherapy agent for metastatic cancers. However, severe adverse effects, including the vascular leak syndrome and the preferential stimulation of anti-immunogenic Treg rather than effector T cells, have been obstacles. We newly designed a mutein IL-2, Mutakine-6 (MK-6), with reduced IL-2Rα-binding capability. MK-6 induced comparable cell growth potential toward IL-2Rßγ-positive T cells but was far less efficient in in vitro Treg proliferation and STAT5 activation. Unlike IL-2, in vivo administration of MK-6 produced minimal adverse effects. Using CT26 and B16F10-syngeneic tumor models, we found MK-6 was highly efficacious on tumor regression. Serum albumin conjugation to MK-6 prolonged in vivo half-life and accumulated in CT26 tumors, showing enhanced antitumor effect. Tumor-infiltrating leukocytes analysis revealed that albumin-fused MK-6 increased the ratio of effector CD8+ T cells to CD4+ Treg cells. These results demonstrated that MK-6 is an efficient immunomodulator potentially used for improved immunotherapy with decreased adverse effects and attenuated Treg stimulation.

Profound Treg perturbations correlate with COVID-19 severity.

The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19-linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.

Identification of CD8+ T Cell-Related Genes: Correlations with Immune Phenotypes and Outcomes of Liver Cancer.

PURPOSE: Treatment outcomes for advanced liver cancer are poor. Immunotherapy is a treatment strategy that has been widely used to treat other cancers. Studies have shown that CD8+ T lymphocytes are essential factors affecting the efficacy of immunotherapy. We used computational biology methods to determine the coexpressed gene network that promotes CD8+ T lymphocyte infiltration. METHOD: We obtained the liver cancer gene matrix and clinical follow-up information data from TCGA liver hepatocellular carcinoma FPKM. We obtained single nucleotide polymorphism (SNP) data to evaluate the tumor mutation burden. The "estimate" package and the CIBERSORT algorithm were used to evaluate tumor purity and the proportion of CD8+ T lymphocytes in the liver cancer cohort. We used the gene expression matrix of liver cancer and the relative proportion of CD8+ T lymphocytes as input files and performed WGCNA based on this analysis. The weighted coexpression network identified the most CD8+ T lymphocyte-related coexpression modules in liver cancer. Then, we analyzed the biological processes involved in the module. We determined the coexpression module with CD8+ T lymphocyte infiltration in terms of data and function. We then screened the factors in the coexpression module correlated with CD8+ T lymphocyte content greater than 0.4. Finally, the expression levels of these factors were verified at the protein level using immunohistochemistry and single-cell sequencing. RESULTS: We determined the CD8+ T lymphocyte proportions that correlated with coexpression networks. Four coexpressed genes (C1QC, CD3D, GZMA, and PSMB9) were identified as CD8+ T cell coexpression genes that promoted infiltration of CD8+ T cells. Because the factors in the coexpression network often participate in similar biological processes, we found that these factors were most related to antigen processing and presentation of peptide antigen through functional enrichment. In the clinical phenotype analysis, we found that 18 factors can be used as independent prognostic protective factors. We found that these factors were significantly negatively correlated with tumor purity and negatively correlated with M2 macrophages in the immunophenotyping analysis. Using immunohistochemistry and single-cell sequencing analysis, we found that CD3D antibody staining was weaker in tumor tissues than normal tissues and was related to CD8+ T cells. CONCLUSION: These coexpressed genes were positively related to the high infiltration proportion of CD8+ T lymphocytes in an antigen presentation process. The biological process might provide new directions for patients who are insensitive to immune therapy.

Infiltration of Immune Competent Cells into Primary Tumors and Their Surrounding Connective Tissues in Xenograft and Syngeneic Mouse Models.

To fight cancer more efficiently with cell-based immunotherapy, more information about the cells of the immune system and their interaction with cancer cells in vivo is needed. Therefore paraffin wax embedded primary breast cancers from the syngeneic mouse WAP-T model and from xenografted tumors of breast, colon, melanoma, ovarian, neuroblastoma, pancreatic, prostate, and small cell lung cancer were investigated for the infiltration of immunocompetent cells by immunohistochemistry using antibodies against leukocyte markers. The following markers were used: CD45 as a pan-leukocyte marker, BSA-I as a dendritic cell marker, CD11b as an NK cell marker, and CD68 as a marker for macrophages. The labeled immune cells were attributed to the following locations: adjacent adipose tissue, tumor capsule, intra-tumoral septae, and cancer cells directly. In xenograft tumors, the highest score of CD45 and CD11b positive, NK, and dendritic cells were found in the adjacent adipose tissue, followed by lesser infiltration directly located at the cancer cells themselves. The detected numbers of CD45 positive cells differed between the tumor entities: few infiltrating cells in breast cancer, small cell lung cancer, neuroblastoma, a moderate infiltration in colon cancer, melanoma and ovarian cancer, strongest infiltration in prostate and pancreatic cancer. In the syngeneic tumors, the highest score of CD45 and CD11b positive, NK and dendritic cells were observed in the tumor capsule, followed by a lesser infiltration of the cancer tissue. Our findings argue for paying more attention to investigate how immune-competent cells can reach the tumor cells directly.

The Prognostic Value of Tumor Mutation Burden and Immune Cell Infiltration in Thymic Epithelial Tumors.

OBJECTIVE: The question of whether the tumor mutation burden (TMB) is associated with either improved survival outcomes or improvement of immunotherapies remains controversial in various malignancies. The aim of this study is to investigate the genomic landscape of the relationship between TMB and immune cell infiltration in thymic epithelial tumors (TETs). METHODS: We downloaded somatic mutation data, transcriptome sequencing data, and clinical information of TETs from the Cancer Genome Atlas (TCGA) database. We assessed the abundance of 22 immune fractions between low-TMB (TMB-L) and high-TMB (TMB-H) groups using the "CIBERSORT" package. RESULTS: Missense mutation had the highest frequency of mutation among the nine variant classifications in TETs. Higher TMB levels were associated with poor survival outcomes (P<0.05), and higher Masaoka stages (P<0.05). More importantly, TMB levels were much higher in the thymic cancer than in thymoma (P<0.01). The infiltration levers of naive CD4(+) T cells and regulatory T cells were significantly higher in the TMB-L group than in the TMB-H group, and this was further associated with better overall survival (OS) in patients with TETs. CONCLUSION: The present study indicates that the prognosis of TMB-H patients with TETs is significantly poorer than is that of TMB-L patients, which might result from the different levels of infiltration of naive CD4(+) T cells and regulatory T cells.

Promises and challenges of adoptive T-cell therapies for solid tumours.

Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas-cancer genomics, cancer immunology and cell-therapy manufacturing-that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.

Pathological Complete Remission of Liver Metastases Correlates With Elimination of Tumor-infiltrating Tregs in Gastric Cancer.

BACKGROUND/AIM: Tumor-infiltrating Foxp3+ regulatory T-cells (Ti-Tregs) promote tumor progression and contribute to poor prognosis in gastric cancer, but the relationship between Ti-Tregs and response to chemotherapy for liver metastases from gastric cancer (LMGC) is unclear. We estimated the correlation between pathological response to chemotherapy and Ti-Tregs in LMGC. PATIENTS AND METHODS: Ti-Tregs were analyzed with immunohistochemistry as CD3+ Foxp3+ cells in patients with synchronous LMGC. RESULTS: Of 53 patients with LMGC, 49 received chemotherapy as initial treatment and 10 underwent R0 resection. LMGC disappeared pathologically in 5 resected cases despite radiologically residual disease. Ti-Tregs were found frequently in residual LMGC and primary lesions but rarely in tumor scar tissue. There was no relationship between frequency of CD8+ cells and pathological response. CONCLUSION: Marked reduction in Ti-Tregs correlates with pathological complete remission of LMGC. Ti-Tregs may be a biomarker to predict the effects of chemotherapy when used in combination with radiological findings.

Cross-platform comparison of immune-related gene expression to assess intratumor immune responses following cancer immunotherapy.

Neoadjuvant immunotherapy can induce immune responses within the tumor microenvironment. Gene expression can be used to assess responses with limited amounts of conventionally-fixed patient-derived samples. We aim to assess the cross-platform concordance of immune-related gene expression data. We performed comparisons across three panels in two platforms: Nanostring nCounter® PanCancer Immune Profiling Panel (nS), HTG EdgeSeq Oncology Biomarker Panel (HTG OBP) and Precision Immuno-Oncology Panel (HTG PIP). All tissue samples of 14 neoadjuvant GM-CSF treated, 14 neoadjuvant Provenge treated, and 12 untreated prostate cancer patients were radical prostatectomy (RP) tissues, while 6 prostatitis patients and 6 non-prostatitis subjects were biopsies. For all 52 patients, more than 90% of the common genes were significantly correlated (p < 0.05) and more than 76% of the common genes were highly correlated (r > 0.5) between any two panels. Co-inertia analysis also demonstrated high overall dataset structure similarity (correlation>0.84). Although both dimensionality reduction visualization analysis and unsupervised hierarchical cluster analysis for highly correlated common genes (r > 0.9) suggested a high-level of consistency across the panels, there were subsets of genes that were differentially expressed across the panels. In addition, while the effect size of the differential testing for neoadjuvant treated vs. untreated localized prostate cancer patients across the panels were significantly correlated, some genes were only differentially expressed in the HTG panels. Finally, the HTG PIP panel had the best classification performance among the 3 panels. These differences detected may be a result of the different panels or platforms due to their technical setting and focus. Thus, researchers should be aware of those potential differences when deciding which platform and panel to use.

The Factors Affecting Expansion of Reactive Tumor Infiltrating Lymphocytes (TIL) From Bladder Cancer and Potential Therapeutic Applications.

Tumor infiltrating lymphocytes (TIL) therapy was shown to provide durable objective response in patients with metastatic melanoma. As a fundamental first step to bring TIL therapy to clinical use, identification of patients whose tumors yield optimal numbers of reactive TIL is indispensable. We have previously shown that expansion of tumor reactive TIL from primary bladder tumors and lymph node metastases is feasible. Here, we performed TIL harvesting from additional surgical specimens (additional 31 primary tumors and 10 lymph nodes) to generate a heterogenous cohort of 53 patients with bladder cancer (BC) to evaluate the tumor characteristics that lead to tumor-reactive TIL expansion. Among a total of 53 patients, overall TIL growth from tumor samples were 37/53 (69.8%) and overall anti-tumor reactive TIL were 26/35 (74.3%). Mixed urothelial carcinoma is associated with higher anti-tumor reactivity of expanded TIL than pure urothelial carcinoma (89.5% vs. 56.3%, p=0.049). The anti-tumor reactivity of expanded TIL from primary tumors previously treated with BCG immunotherapy were lower (33.3% vs. 82.6%, p=0.027) although T-cell phenotype (CD3+, CD4+, CD8+, and CD56+) was similar regardless prior of BCG therapy. Addition of agonistic 4-1BB antibody in culture media with IL-2 improved the number of expanded TIL from primary tumors previously treated with BCG immunotherapy. There was no significant difference between basal and luminal subtype tumors in terms of viable and reactive TIL growth. Our study demonstrates that TIL expansion is feasible across all BC patients and BC subtypes, and we suggest that TIL therapy can be a reasonable treatment strategy for various manifestations of BC.

BIRC5 is a prognostic biomarker associated with tumor immune cell infiltration.

BIRC5 is an immune-related gene that inhibits apoptosis and promotes cell proliferation. It is highly expressed in most tumors and leads to poor prognosis in cancer patients. This study aimed to analyze the relationship between the expression level of BIRC5 in different tumors and patient prognosis, clinical parameters, and its role in tumor immunity. Genes co-expressed with BIRC5 were analyzed, and functional enrichment analysis was performed. The relationship between BIRC5 expression and the immune and stromal scores of tumors in pan-cancer patients and the infiltration level of 22 tumor-infiltrating lymphocytes (TILs) was analyzed. The correlation of BIRC5 with immune checkpoints was conducted. Functional enrichment analysis showed that genes co-expressed with BIRC5 were significantly associated with the mitotic cell cycle, APC/C-mediated degradation of cell cycle proteins, mitotic metaphase, and anaphase pathways. Besides, the high expression of BIRC5 was significantly correlated with the expression levels of various DNA methyltransferases, indicating that BIRC5 regulates DNA methylation. We also found that BIRC5 was significantly correlated with multiple immune cells infiltrates in a variety of tumors. This study lays the foundation for future research on how BIRC5 modulates tumor immune cells, which may lead to the development of more effective targeted tumor immunotherapies.

Immune signature of tumor-infiltrating immune cells predicts the prognosis and therapeutic effects in squamous cell carcinoma.

Tumor-infiltrating immune cells (TICs) are involved in tumor progression and determine the prognosis. We investigated how TICs affect the prognosis and therapeutic effects of squamous cell carcinoma (SCC), which share common histological features and certain risk factors. The SCC data from The Cancer Genome Atlas (TCGA) and Gene expression Omnibus (GEO) databases were downloaded to evaluate the composition of TICs with the CIBERSORT algorithm. LASSO and Cox multivariate regression analyses were used to build a prognostic risk model. Chemotherapeutic and immunotherapeutic responses were compared between patients with SCC. A Gene set variation analysis (GSVA) was also performed to elucidate the mechanism. Naïve B cells and resting mast cells were selected to construct the prognostic model. According to these two immune cell subtypes, patients with SCC were divided into low- and high-risk groups. The low-risk group with high proportions of naïve B cells and resting mast cells had a better overall survival rate than the high-risk group and might benefit from immunotherapy and chemotherapy due to differences in the immune microenvironment. Activation of the Wnt signaling pathway was observed in the high-risk group. Based on the findings from the present study, the immune signature provides prognostic determinants of SCC and may be a biomarker to guide chemotherapy and immunotherapy. Wnt inhibitors may be attractive candidates for combination treatment in high-risk patients with SCC.

Prognostic value of tumor-infiltrating lymphocyte subtypes in residual tumors of patients with triple-negative breast cancer after neoadjuvant chemotherapy.

BACKGROUND: After neoadjuvant chemotherapy (NAC), non-pathological complete response of breast cancer patients can benefit from tailored adjuvant chemotherapy. However, it is difficult to select patients with poorer prognosis for additional adjuvant chemotherapy to maximize the benefits. Our study aimed to explore whether the subtypes of tumor-infiltrating lymphocytes (TILs) in residual tumors (RT) is related to the prognosis of triple-negative breast cancer (TNBC) after NAC. METHODS: Data from patients with primary TNBC consecutively diagnosed at the Breast Disease Center of Peking University First Hospital from 2008 to 2014 were retrieved, and the cases with RT in the breast after NAC were enrolled. TILs subtypes in RT were observed by double-staining immunohistochemistry, and counted with the median TILs value per square millimeter as the cut-off to define high versus low TILs density in each subtype. The relationships between the TIL density of each subgroup and the clinicopathological characteristics of the RT after NAC patients were analyzed by Fisher exact test. Disease-free survival (DFS) and overall survival (OS) were analyzed by the Kaplan-Meier method and log-rank statistics. RESULTS: A total of 37 eligible patients were included in this study, and the median follow-up period was 50 months (range 17-106 months). There was no significant correlation between the infiltrate density of CD4, CD8, CD20, and CD68 lymphocytes and clinic-pathological characteristics. Significantly better prognosis was observed in patients with high CD4-TILs (DFS: P = 0.005, OS: P = 0.021) and high CD8-TILs (DFS: P = 0.018) and low CD20-TILs (OS: P = 0.042). Further analysis showed that patients with CD4/CD20 ratio greater than 1 (DFS: P = 0.001, OS: P = 0.002) or CD8/CD20 ratio greater than 1 (DFS: P = 0.009, OS: P = 0.022) had a better prognosis. CONCLUSIONS: Subtypes of TILs in RT is a potential predictive biomarker of survival in TNBC patients after NAC.

Colorectal Cancer Biology, Diagnosis, and Therapeutic Approaches.

Colorectal cancer (CRC) is the second most diagnosed disease worldwide. It is the fourth leading cause of cancer related mortalities. Higher probability for the occurrence of CRC is due to western lifestyle, age, and personal history of chronic diseases. The development of CRC is a multistep process that includes a sequence of genetic, histological, and morphological alterations that accumulate over time. Furthermore, depending on the origin of mutations, CRC can be classified as familial, sporadic, and inherited, based on which a therapeutic plan is created for a CRC patient. These mutations cause chromosomal alterations and translocations in genes that lead to microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and chromosomal instability (CIN). The mutations affect dysregulation of various pathways that are responsible for cancer progression. They include the PI3K/Akt, Wnt, TP53, and MAPK pathways. Mutated genes, such as KRAS, PTEN, SMAD4, BRAF, and PTEN, are employed as predictive biomarkers for early diagnosis. The conventional therapies of CRC start with surgical resection followed by adjuvant therapies, such as radiotherapy and chemotherapy. Researchers are now developing therapies that combine triplet drugs to overcome the hurdle of multidrug resistance (MDR). The combination of chemotherapy with immunotherapy to target the dysregulated proteins, such as EGFR and VEGFR is found efficient for advanced mCRC therapy. Researchers are now developing personalized medicines by detecting and validating key biomarkers to understand the mechanism of MDR and toxicity. In this review, we address genetic alterations, current data on biomarkers, and novel therapeutic approaches for the treatment of CRC.

Role of cancer immunology in chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is caused by the BCR-ABL chimeric tyrosine kinase, which is derived from the reciprocal translocation, t(9;22)(q34;q11). BCR-ABL tyrosine kinase inhibitors (TKIs) can provide prolonged overall survival in CML patients, resulting in life expectancy nearly to general population, and now approximately half of patients who achieved deep molecular response (DMR) can sustain durable molecular remission after discontinuation TKIs. However, residual leukemic cells still detected in the patients who sustained in molecular remission after discontinuation TKIs with the sensitive BCL-ABL1 transcript detection method. Given the fact that residual leukemic cells can exist in these patients, host immune systems can protect the patients to develop CML progression derived from residual leukemic cells. The human immune system is generally composed by innate and adaptive immune systems, corresponding to their functional diversities. Natural killer (NK) cells are major components of the innate immune system, while T lymphocytes (T cells) are major components of the adaptive immune system, and both NK cell and T cell mediate immune responses have an important role in CML. Myeloid-derived suppressor cells (MDSCs) that promote expansion of regulatory T cells (Tregs), leading to host immune suppression, are also important. Although regulation mechanism of these immune system has not been fully elucidated, tumor antigen (e.g. Wilms tumor-1), and surface receptors (e.g. killer immunoglobulin-like receptor and natural killer group 2) on NK cells, are pivotal role in these immune system regulations. Hence, we reviewed the current the immunological analysis, especially T cell and NK cell immunity in CML.

Tumor infiltrating lymphocytes in malignant melanoma - allies or foes?

This is an overview of current problematics regarding the role of tumor infiltrating lymphocytes (TILs) in malignant melanomas. Various and often conflicting data have been published, correlating tumor type, stage, prognosis, as well as sex and age of patients. This is partly due to heterogeneity in scaling systems and unstandardized TILs grading but also due to changes of tumor-host interactions. Melanomas are an immunologically heterogeneous group with variability of TILs, where distinct gene expression patterns were found in tumors with absent, and/or non- brisk TIL grade versus brisk TIL grade. However, the presence of TILs alone appears to be inadequate for implicating them as immunologically functional. Further characterisation of TIL phenotype and function is warranted. This especially concerns, evaluation of TILs of the suppressor phenotype but rather than as a prognostic factor, more for prediction of targeted immunotherapy.