This editorial will focus on tumor immunity and the factors that alter the tumor immune micro-environment.The role of tumor infiltrating lymphocytes(TILs)will also be discussed in detail,including the types,mechanism ...This editorial will focus on tumor immunity and the factors that alter the tumor immune micro-environment.The role of tumor infiltrating lymphocytes(TILs)will also be discussed in detail,including the types,mechanism of action,and role.Gastric cancer(GC)often presents in the advanced stage and has various factors predicting the outcomes.The interplay of these factors and their correlation with the TILs is discussed.A literature review revealed high intratumoral TILs associated with higher grade,HER2-,and Helicobacter pylori negativity.Moreover,stromal(ST)TILs correlated with lower grade and lesser recurrence risk in GC.High TILs in ST and invasive border also correlated with mismatch repair deficiency status.Further characterization of the CD3+,CD8+,and other cells is also warranted.In the future,this complex correlation of cancer cells with the immune system can be explored for therapeutic avenues.展开更多
Tumor infiltrating lymphocytes (TILs) are used in evaluating the prognosis and determining treatment of different types of cancer with variable degrees of success. The usage of checkpoint inhibitor immunotherapy as a ...Tumor infiltrating lymphocytes (TILs) are used in evaluating the prognosis and determining treatment of different types of cancer with variable degrees of success. The usage of checkpoint inhibitor immunotherapy as a treatment variety for cancer and Adoptive cell therapy is associated with many complications, severe side effects and high expenses. Recently, in a limited number of metastatic GIT and breast cancers, the identification of T-cell specific against so-called tumor neo-antigens and Adoptive transfer of those lymphocytes resulted in some improvement. In 2020, Detection of a T cell receptor (TCR) in a T cell clone that recognized and killed most human cancer cell lines in vitro via the monomorphic MHC class I-related protein MR1, offers an opportunity for pan-cancer therapy Twenty three years earlier, Moist Heat was used successfully to activate a whole different and new immune response that was able to detect genetic mutation in the affected cancer cells and cured many cases of squamous and basal cell carcinomas. In this commentary review, we aimed to revise the literature for updates of TILs usage in cancer prognosis and treatment.展开更多
Establishing Epstein-Barr virus (EBV)-specific cytolytic T lymphocytes (EBV-CTLs) from peripheral blood mononuclear cells (PBMCs) for adoptive immunotherapy has been reported in EBV-associated malignancies including H...Establishing Epstein-Barr virus (EBV)-specific cytolytic T lymphocytes (EBV-CTLs) from peripheral blood mononuclear cells (PBMCs) for adoptive immunotherapy has been reported in EBV-associated malignancies including Hodgkin's lymphoma and nasopharyngeal carcinoma (NPC). In the current study,we performed ex vivo expansion of tumor-infiltrating lymphocytes (TILs) obtained from NPC biopsy specimens with a rapid expansion protocol using anti-CD3 monoclonal antibody (OKT3), recombinant human interleukin (IL)-2, and irradiated PBMCs from healthy donors to initiate the growth of TILs. Young TIL cultures comprised of more than 90% of CD3+T cells, a variable percentage of CD3+CD8+and CD3+CD4+T cells, and less than 10% of CD3-CD16+natural killer cells, a similar phenotype of EBV-CTL cultures from PBMCs. Interestingly, TIL cultures secreted high levels of the Th1 cytokines, interferon gamma (IFNγ) and tumor necrosis factor-alpha (TNF-α), and low levels of the Th2 cytokines, IL-4 and IL-10. Moreover, young TILs could recognize autologous EBV-transformed B lymphoblast cell lines, but not autologous EBV-negative blast cells or allogeneic EBV-negative tumor cells. Taken together, these data suggest that ex vivo expansion of TILs from NPC biopsy tissue is an appealing alternative method to establish T cell-based immunotherapy for NPC.展开更多
Immunotherapy has begun to revolutionize cancer treatment, by introducing therapies that target the host immune system instead of the tumor, therapies that possess unique adverse event profiles, and therapies that may...Immunotherapy has begun to revolutionize cancer treatment, by introducing therapies that target the host immune system instead of the tumor, therapies that possess unique adverse event profiles, and therapies that may cure certain types of cancer. The immune microenvironment of tumors is emerging as the most important means of understanding the relationship between a patient' immune system and their cancer, informing prognosis, and guiding immunotherapy, such as an antibody blockade of immune checkpoints. For some solid tumors, simple quantitation of lymphocyte infiltration would seem to have prognostic significance, suggesting that lymphocyte infiltration is not passive but may actively promote or inhibit tumor growth. For gastric cancers, several studies have provided strong evidence that immune cells contribute to determining prognosis. However, the exact role of immune cells in gastric cancer remains unclear. Therefore, this review focuses on the clinical significance of immune cells, especially tumor-infiltrating lymphocytes, in gastric cancer.展开更多
AIM To determine influence of neoadjuvant-chemotherapy(NAC) over tumor-infiltrating-lymphocytes(TIL) intriple-negative-breast-cancer(TNBC).METHODS TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de...AIM To determine influence of neoadjuvant-chemotherapy(NAC) over tumor-infiltrating-lymphocytes(TIL) intriple-negative-breast-cancer(TNBC).METHODS TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays(TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant. RESULTS Higher TIL evaluated in full-face sections from pre-NAC tumors was associated to pathologic-complete-response(pCR)(P = 0.0251) and outcome(P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections(ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. PostNAC lesions with pC R had similar TIL levels than those without pCR(P = 0.6331). NAC produced a TIL decrease in full-face sections(P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival(DFS). Higher counts of CD3 in pre-NAC samples had longer overallsurvival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR.CONCLUSION TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related.展开更多
Tumor-infiltrating lymphocytes (TIL)isolated from metastatic lymph nodes in patients with nonoperable advanced gastric cancer were induced to become LAK-like cytotoxic activrty of TIL after in vitro culture with rlL-2...Tumor-infiltrating lymphocytes (TIL)isolated from metastatic lymph nodes in patients with nonoperable advanced gastric cancer were induced to become LAK-like cytotoxic activrty of TIL after in vitro culture with rlL-2.Twenty-three patients with advanced gastric cancer were treated by intravenously transfer of autologous TIL combined with rlL-2. The tumor forus disappeared (complete remission, CR) in 3 patients (13. 0%) and significantly decreased (partial remission, PR) in 5 patients (21. 7%). Fifteen patients did not respond to the treatment. The amount of soluable IL-2 receptor in serum was significantly decreased after treatment, the cytotoxicity of NK cells and OT test were significantly increased. No significant difference in CD4/CD8 was found between before and after treatment. No serious side effect was obseved in the treatment.展开更多
In order to study the significance of FasL expression in immune escape of breast cancer, FasL protein expression and the number of tumor-infiltrating lymphocytes (TILs) in 40 specimens of breast cancer were detected...In order to study the significance of FasL expression in immune escape of breast cancer, FasL protein expression and the number of tumor-infiltrating lymphocytes (TILs) in 40 specimens of breast cancer were detected by immunohistochemitry. The expression of FasL mRNA was measured by in situ hybridization in the consecutive tissue slices of 40 breast cancers respectively. By using terminal deoxynucleotidyl transferase-mediaed dUTP nick end labeling (TUNEL), apoptotic cells were detected in 40 specimens of breast cancer. The expression of FasL was detected in all 40 specimens to varying degrees. In the consecutive tissue slices, the location of expression of FasL protein corresponded with that of FasL mRNA. In those with FasL extensive expression, the number of TILs was less (P〈0.05), the apoptotic index (AI) of TILs was higher and the AI of tumor cells was lower (P〈0.01) than those with FasL weak expression respectively. The AI of TILs was correlated with that of tumor cells (r=-0.629, P〈0.01). In conclusion, breast cancer cells can induce the apoptosis of TILs through the expression of FasL, which can counterattack the immune system. This may be a mechanism of immune evasion in breast cancer.展开更多
In this study, the isolation, purification and differentiation of tumor-lnflltratlng lymphocytes (TIL) from 6 fresh osteosarcoma specimens were achieved by discontinuous density gradient centrifugation. One specimen o...In this study, the isolation, purification and differentiation of tumor-lnflltratlng lymphocytes (TIL) from 6 fresh osteosarcoma specimens were achieved by discontinuous density gradient centrifugation. One specimen of the osteosarcoma TIL were enlarged in IL-2 for long time in vitro, reaching 28 days and their cytolytic activity against different tumor cell lines was Investigated. The experimental results indicated that the preparation of osteosarcoma TIL adopted by the mechanical means was simple, having higher purifity, keeping higher effects on killing NK- sensitive tumor cell lines and NK-insensitive tumor cell lines as well as rapid proliferation in vitro cultured in IL-2.展开更多
By uaing enzyme digestion and Flcoll- Hypaque or Percoll discontinuous density methods, we have successfully obtained tumor-infiltrating lymphocytes (TIL) from mouse hepatoma. When analyzing the purity of TIL after se...By uaing enzyme digestion and Flcoll- Hypaque or Percoll discontinuous density methods, we have successfully obtained tumor-infiltrating lymphocytes (TIL) from mouse hepatoma. When analyzing the purity of TIL after separation. It was found that Percoll was more effective than Flcoll (P<0. 01). TIL could be activated In the presence of recombinant lL-2 (rIL-2) and begin to expand after culturing for 5-7 days, the tumor cells tend to decrease and disappeared after 14 days or so. TIL increased 105-fold over 40 days. Conditioned medium containing supernatant of PHA and rIL- 2 stimulated syngeneic spleen cell culture could promote the expansion of TIL.展开更多
BACKGROUND Tumor-infiltrating lymphocytes(TILs)constitute a prognostic factor in hepatocellular carcinoma(HCC).However,different methods of assessing TILs have various pre-analytical,analytical,and post-analytical cha...BACKGROUND Tumor-infiltrating lymphocytes(TILs)constitute a prognostic factor in hepatocellular carcinoma(HCC).However,different methods of assessing TILs have various pre-analytical,analytical,and post-analytical challenges.The evaluation of TILs in hematoxylin and eosin(H&E)-stained tumor sections proposed by the International Immuno-Oncology Biomarker Working Group was demonstrated to be a reproducible,affordable and easily applied method in many tumors.AIM To evaluate the prognostic significance of TILs in H&E-stained slides of HCCs.METHODS This was a retrospective study performed in the hospital.HCC patients who underwent liver resection between 2015 and 2017 in Zhongshan Hospital were enrolled in this study.Patients who experienced recurrence or received therapy in addition to antiviral therapy before surgery at this time were excluded.A total of 204 patients were enrolled in the study.The ILs were counted manually in tumor sections stained with H&E under an optical microscope at 400×.The ILs were assessed separately in the center of the tumor(TILs^(CT)),the invasive front(TILs^(IF)),and peritumor(PILs)areas.Univariate and multivariate survival analyses were performed using a Cox regression model.P<0.05 was considered statistically significant and all P-values were two-sided.RESULTS Among the 204 patients,univariate analysis indicated that macrovascular invasion(MaVI)(P=0.001),microvascular invasion(MVI)(P=0.012),multiple tumors(P=0.008),large tumors(>10 cm)(P=0.001),absence of a tumor capsule(P=0.026),macrotrabecular histological subtype(P=0.001),low density of TILs^(CT)(P=0.039),TILs^(IF)(P=0.014),and PILs(P=0.010)were predictors of progressionfree survival(PFS).Cox multivariate analysis indicated that MaVI(P=0.009),absence of a tumor capsule(P=0.031),low-density of TILs^(IF)(P=0.047)and PILs(P=0.0495)were independent predictors of PFS.A three-category analysis was carried out by combining TILs^(CT),TILs^(IF),and PILs,after which HCCs were classified into immune^(high)[(TILs^(CT))^(high),(TILs^(IF))^(high),and PILs^(high),83 cases],immune^(mod)(tumors other than immune^(high) and immune^(low) subtypes,94 cases),and immune^(low)[(TILs^(CT))^(low),(TILs^(IF))^(low),and PILs^(low),27 cases]subtypes.The immune^(high) subtype had a lower rate of MVI(40.96%)than the immune^(mod)(61.70%,P=0.017)and immune^(low)(66.67%,P=0.020)subtypes.The recurrence rates of the immune^(high),immune^(mod) and immune^(low) subtypes were 10.8%,25.5%and 33.3%,respectively.CONCLUSION HCC patients with high infiltrating lymphocytes tend to have a lower recurrence rate and less MVI.The evaluation of TILs in H&E-stained specimens could be a prognostic parameter for HCC.展开更多
Objective: To study immunologic character of tumor-infiltrating lymphocytes (TIL) on postin vitro expansion in ovarian carcinoma, and evaluate the prospects by adopting TIL treatment of ovarian carcinoma at an advance...Objective: To study immunologic character of tumor-infiltrating lymphocytes (TIL) on postin vitro expansion in ovarian carcinoma, and evaluate the prospects by adopting TIL treatment of ovarian carcinoma at an advanced stage. Methods: Cellular phenotype changes in TIL were analyzed by flow cytometry. By means of molecular biology and immunologic methods, ability to secrete cytokines and anti-tumor activities of in TIL was studied. Results: Difference of cellular phenotypes in TIL was probably related to the type, feature and resource of the tumor. TIL obtained from phoroplast and parenchyma was dominant in CD3+CD4+. TIL obtained from tumor tissues, around microvessels and ascitic fluid was dominant in CD3+CD8 Concentration of rIL-2in vitro played a significant role in immunologic character of TIL. By means of rIL-2 expansionin vitro, TIL has apparently been improved in competence of secreting some cytokines, such as IL-2, TNF-α, IFN-γ, and anti-tumor activities. The activated TIL was more stimulated by further adding anti-CD3 or PHA (suitable concentration), which significantly increased its ability to secrete cytokines. Treatment with TIL+CTX or TIL+ rIL-2, could apparently improve phenotypes in peripheral blood of patients, with definitive effects. Conclusion: Immunologic activities of TILin vitro are apparently improved by rIL2 expansion. Regression of tumor, by means of infusion TIL, is not largely attributed to direct cytotoxicity to tumor cells, but indirectly and partly augmenting cellular activities and abilities of immunomodulation in patients with ovarian carcinoma being dependent on secreting multiple cytokines.展开更多
Primary tumor tissues in the digestive system were harvested form 15 patients. By mincing,enzymatic digestion and gradient density separation, sufficient TILs(>5×106) were obtained from 13 of 15 (88.7%) patien...Primary tumor tissues in the digestive system were harvested form 15 patients. By mincing,enzymatic digestion and gradient density separation, sufficient TILs(>5×106) were obtained from 13 of 15 (88.7%) patients in vitro in the presence of 500 μ/ml of recombinant interleukin-2 and 5% fetal calf serum after one month culture. 92.3% (12/13) of TILs proliferated well in vitro (92.3%). TILs expanded from 102-folds to 103-folds after being cultured for one month. CD25+ cell of the most fresh TILs was more than that of peripheral blood lymphocytes. CD25+ cells of TILs during 4th week of the culture was significantly greater (P<0.01) than that of fresh TILs. CD4+/CD8+ ratio was decreased during four culture weeks because of increase of CD8 cells. By using modified colorimetric MTT assay for measuring activity of TILs against various tumor cells the results showed that cytotoxicity of gastro-intestinal TILs autologous tumor cells is greater than on the other tumor cells.展开更多
Objective: To study the effect of tumor infiltrating lymphocytes at cancer nest on local control of rectal cancer after preoperative radiotherapy. Methods: From Jan. 1999 to Oct. 2007, a total of 107 patients with r...Objective: To study the effect of tumor infiltrating lymphocytes at cancer nest on local control of rectal cancer after preoperative radiotherapy. Methods: From Jan. 1999 to Oct. 2007, a total of 107 patients with rectal cancer were reviewed. They were treated by preoperative radiotherapy, 30 Gy/10 fractions/12 days. Two weeks later, the patient underwent a surgical operation. Their pathological samples were kept in our hospital before and after radiotherapy. Lymphocyte infiltration (LI) degree, pathologic degradation and fibrosis degree after radiotherapy in paraffin section were evaluated under microscope. Results: After followed-up of 21 months (2-86 months), a total of 107 patients were reviewed. Univariate analysis showed that lymphocyte infiltration (LI), fibrosis and pathologic changes after radiotherapy were significant factors on local control. Logistic regression analysis showed that LI after radiotherapy was a significant effect factor on local control. Conclusion: LI, fibrosis and pathologic degradation after radiotherapy are significant for local control of rectal cancer after preoperative radiotherapy. LI after radiotherapy was a significantly prognostic index for local control of rectal cancer after preoperative radiotherapy.展开更多
BACKGROUND Tumor budding(TB)has emerged as a promising independent prognostic biomarker in colorectal cancer(CRC).The prognostic role of TB has been extensively studied and currently affects clinical decision making i...BACKGROUND Tumor budding(TB)has emerged as a promising independent prognostic biomarker in colorectal cancer(CRC).The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC.However,existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies.Consequently,this study investigated the correlation among TB categories,clinicopathological features,and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification.AIM To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC.METHODS The clinical data of 547 CRC patients were collected for this retrospective study.Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines.RESULTS Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy(P=0.004),clinical stage IV(P<0.001),≥4 regional lymph node metastases(P=0.004),left-sided colonic cancer(P=0.040),and Bd 2-3(P=0.002)were independent prognostic factors in patients with stage III-IV CRC.Moreover,the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3,both in the tumor stroma and its invasive margin.CONCLUSION TB has an independent predictive prognostic value in patients with stage III-IV CRC.It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.展开更多
AIM: To investigate the morphological characterization of tumor infiltrating dendritic cells (TIDCs) and tumor infiltrating lymphocytes (TILs) in human rectal cancer. METHODS: Light and electron microscopy as we...AIM: To investigate the morphological characterization of tumor infiltrating dendritic cells (TIDCs) and tumor infiltrating lymphocytes (TILs) in human rectal cancer. METHODS: Light and electron microscopy as well as immunohistochemistry were used to observe the distributive and morphological changes of TIDCs and TILs. RESULTS: TIDCs were mainly located in tumor-surrounding tissue. The number of TIDCs in the earlier stage was higher than that in the later stage (P〈 0.01). TILs were mainly seen in adjacent tissue of cancers and tumor-surrounding tissue. There were more TILs in the earlier stage than that in the later stage (P〈0.01). Under electron microscope, TIDCs were irregular in shape and exhibited many dendritic protrusions. It isn't obvious that cancer cells perforated the basement membrane and TILs were arranged along the basement membrane in the earlier stage. In the later stage, it is explicit that cancer cells perforated the basement membrane and surrounded by TILs. There were contacts among TIDCs, TILs and tumor cell. One IIDCs contacted one or several TILs which clustered around TIDCs. Glycogen granules were seen between TIDCs and Tits. CONCLUSION: The number of TIDCs and TILs is related with tumor progression There exist close relationships among TIDCs, TILs and tumor cell.展开更多
Objective: To elucidate the role and prognostic significance of lymphocyte activation-gene-3(LAG-3) in soft tissue sarcoma(STS).Methods: The expression of LAG-3 in patient and matched normal blood samples was analyzed...Objective: To elucidate the role and prognostic significance of lymphocyte activation-gene-3(LAG-3) in soft tissue sarcoma(STS).Methods: The expression of LAG-3 in patient and matched normal blood samples was analyzed by flow cytometry. The localization and prognostic values of LAG-3^+ cells in 163 STS patients were analyzed by immunohistochemistry. In addition, the expression of tumor-infiltrating CD3^+ T, CD4^+ T, and CD8^+ T cells and their role in the prognosis of STS were evaluated by immunohistochemistry. The effect of LAG-3 blockade was evaluated in an immunocompetent MCA205 fibrosarcoma mouse model.Results: Peripheral CD8^+ and CD4^+ T cells from STS patients expressed higher levels of LAG-3 than those from healthy donors.LAG-3 expression in STS was significantly associated with a poor clinical outcome(P = 0.038) and was correlated with high pathological grade(P < 0.001), advanced tumor stage(P = 0.016). Additionally, LAG-3 expression was highly correlated with CD8^+ T-cell infiltration(r = 0.7034, P < 0.001). LAG-3 was expressed in murine tumor-infiltrating lymphocytes, and its blockade decreased tumor growth and enhanced secretion of interferon-gamma by CD8^+ and CD4^+ T cells.Conclusions: LAG-3 blockade may be a promising strategy to improve the effects of targeted therapy in STS.展开更多
文摘This editorial will focus on tumor immunity and the factors that alter the tumor immune micro-environment.The role of tumor infiltrating lymphocytes(TILs)will also be discussed in detail,including the types,mechanism of action,and role.Gastric cancer(GC)often presents in the advanced stage and has various factors predicting the outcomes.The interplay of these factors and their correlation with the TILs is discussed.A literature review revealed high intratumoral TILs associated with higher grade,HER2-,and Helicobacter pylori negativity.Moreover,stromal(ST)TILs correlated with lower grade and lesser recurrence risk in GC.High TILs in ST and invasive border also correlated with mismatch repair deficiency status.Further characterization of the CD3+,CD8+,and other cells is also warranted.In the future,this complex correlation of cancer cells with the immune system can be explored for therapeutic avenues.
文摘Tumor infiltrating lymphocytes (TILs) are used in evaluating the prognosis and determining treatment of different types of cancer with variable degrees of success. The usage of checkpoint inhibitor immunotherapy as a treatment variety for cancer and Adoptive cell therapy is associated with many complications, severe side effects and high expenses. Recently, in a limited number of metastatic GIT and breast cancers, the identification of T-cell specific against so-called tumor neo-antigens and Adoptive transfer of those lymphocytes resulted in some improvement. In 2020, Detection of a T cell receptor (TCR) in a T cell clone that recognized and killed most human cancer cell lines in vitro via the monomorphic MHC class I-related protein MR1, offers an opportunity for pan-cancer therapy Twenty three years earlier, Moist Heat was used successfully to activate a whole different and new immune response that was able to detect genetic mutation in the affected cancer cells and cured many cases of squamous and basal cell carcinomas. In this commentary review, we aimed to revise the literature for updates of TILs usage in cancer prognosis and treatment.
基金supported by grants from the National Natural Science Foundation of China (No.224-30872981)Guangdong Province Natural Science Foundation (No.10151008901000156)
文摘Establishing Epstein-Barr virus (EBV)-specific cytolytic T lymphocytes (EBV-CTLs) from peripheral blood mononuclear cells (PBMCs) for adoptive immunotherapy has been reported in EBV-associated malignancies including Hodgkin's lymphoma and nasopharyngeal carcinoma (NPC). In the current study,we performed ex vivo expansion of tumor-infiltrating lymphocytes (TILs) obtained from NPC biopsy specimens with a rapid expansion protocol using anti-CD3 monoclonal antibody (OKT3), recombinant human interleukin (IL)-2, and irradiated PBMCs from healthy donors to initiate the growth of TILs. Young TIL cultures comprised of more than 90% of CD3+T cells, a variable percentage of CD3+CD8+and CD3+CD4+T cells, and less than 10% of CD3-CD16+natural killer cells, a similar phenotype of EBV-CTL cultures from PBMCs. Interestingly, TIL cultures secreted high levels of the Th1 cytokines, interferon gamma (IFNγ) and tumor necrosis factor-alpha (TNF-α), and low levels of the Th2 cytokines, IL-4 and IL-10. Moreover, young TILs could recognize autologous EBV-transformed B lymphoblast cell lines, but not autologous EBV-negative blast cells or allogeneic EBV-negative tumor cells. Taken together, these data suggest that ex vivo expansion of TILs from NPC biopsy tissue is an appealing alternative method to establish T cell-based immunotherapy for NPC.
文摘Immunotherapy has begun to revolutionize cancer treatment, by introducing therapies that target the host immune system instead of the tumor, therapies that possess unique adverse event profiles, and therapies that may cure certain types of cancer. The immune microenvironment of tumors is emerging as the most important means of understanding the relationship between a patient' immune system and their cancer, informing prognosis, and guiding immunotherapy, such as an antibody blockade of immune checkpoints. For some solid tumors, simple quantitation of lymphocyte infiltration would seem to have prognostic significance, suggesting that lymphocyte infiltration is not passive but may actively promote or inhibit tumor growth. For gastric cancers, several studies have provided strong evidence that immune cells contribute to determining prognosis. However, the exact role of immune cells in gastric cancer remains unclear. Therefore, this review focuses on the clinical significance of immune cells, especially tumor-infiltrating lymphocytes, in gastric cancer.
文摘AIM To determine influence of neoadjuvant-chemotherapy(NAC) over tumor-infiltrating-lymphocytes(TIL) intriple-negative-breast-cancer(TNBC).METHODS TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays(TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant. RESULTS Higher TIL evaluated in full-face sections from pre-NAC tumors was associated to pathologic-complete-response(pCR)(P = 0.0251) and outcome(P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections(ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. PostNAC lesions with pC R had similar TIL levels than those without pCR(P = 0.6331). NAC produced a TIL decrease in full-face sections(P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival(DFS). Higher counts of CD3 in pre-NAC samples had longer overallsurvival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR.CONCLUSION TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related.
文摘Tumor-infiltrating lymphocytes (TIL)isolated from metastatic lymph nodes in patients with nonoperable advanced gastric cancer were induced to become LAK-like cytotoxic activrty of TIL after in vitro culture with rlL-2.Twenty-three patients with advanced gastric cancer were treated by intravenously transfer of autologous TIL combined with rlL-2. The tumor forus disappeared (complete remission, CR) in 3 patients (13. 0%) and significantly decreased (partial remission, PR) in 5 patients (21. 7%). Fifteen patients did not respond to the treatment. The amount of soluable IL-2 receptor in serum was significantly decreased after treatment, the cytotoxicity of NK cells and OT test were significantly increased. No significant difference in CD4/CD8 was found between before and after treatment. No serious side effect was obseved in the treatment.
文摘In order to study the significance of FasL expression in immune escape of breast cancer, FasL protein expression and the number of tumor-infiltrating lymphocytes (TILs) in 40 specimens of breast cancer were detected by immunohistochemitry. The expression of FasL mRNA was measured by in situ hybridization in the consecutive tissue slices of 40 breast cancers respectively. By using terminal deoxynucleotidyl transferase-mediaed dUTP nick end labeling (TUNEL), apoptotic cells were detected in 40 specimens of breast cancer. The expression of FasL was detected in all 40 specimens to varying degrees. In the consecutive tissue slices, the location of expression of FasL protein corresponded with that of FasL mRNA. In those with FasL extensive expression, the number of TILs was less (P〈0.05), the apoptotic index (AI) of TILs was higher and the AI of tumor cells was lower (P〈0.01) than those with FasL weak expression respectively. The AI of TILs was correlated with that of tumor cells (r=-0.629, P〈0.01). In conclusion, breast cancer cells can induce the apoptosis of TILs through the expression of FasL, which can counterattack the immune system. This may be a mechanism of immune evasion in breast cancer.
文摘In this study, the isolation, purification and differentiation of tumor-lnflltratlng lymphocytes (TIL) from 6 fresh osteosarcoma specimens were achieved by discontinuous density gradient centrifugation. One specimen of the osteosarcoma TIL were enlarged in IL-2 for long time in vitro, reaching 28 days and their cytolytic activity against different tumor cell lines was Investigated. The experimental results indicated that the preparation of osteosarcoma TIL adopted by the mechanical means was simple, having higher purifity, keeping higher effects on killing NK- sensitive tumor cell lines and NK-insensitive tumor cell lines as well as rapid proliferation in vitro cultured in IL-2.
文摘By uaing enzyme digestion and Flcoll- Hypaque or Percoll discontinuous density methods, we have successfully obtained tumor-infiltrating lymphocytes (TIL) from mouse hepatoma. When analyzing the purity of TIL after separation. It was found that Percoll was more effective than Flcoll (P<0. 01). TIL could be activated In the presence of recombinant lL-2 (rIL-2) and begin to expand after culturing for 5-7 days, the tumor cells tend to decrease and disappeared after 14 days or so. TIL increased 105-fold over 40 days. Conditioned medium containing supernatant of PHA and rIL- 2 stimulated syngeneic spleen cell culture could promote the expansion of TIL.
文摘BACKGROUND Tumor-infiltrating lymphocytes(TILs)constitute a prognostic factor in hepatocellular carcinoma(HCC).However,different methods of assessing TILs have various pre-analytical,analytical,and post-analytical challenges.The evaluation of TILs in hematoxylin and eosin(H&E)-stained tumor sections proposed by the International Immuno-Oncology Biomarker Working Group was demonstrated to be a reproducible,affordable and easily applied method in many tumors.AIM To evaluate the prognostic significance of TILs in H&E-stained slides of HCCs.METHODS This was a retrospective study performed in the hospital.HCC patients who underwent liver resection between 2015 and 2017 in Zhongshan Hospital were enrolled in this study.Patients who experienced recurrence or received therapy in addition to antiviral therapy before surgery at this time were excluded.A total of 204 patients were enrolled in the study.The ILs were counted manually in tumor sections stained with H&E under an optical microscope at 400×.The ILs were assessed separately in the center of the tumor(TILs^(CT)),the invasive front(TILs^(IF)),and peritumor(PILs)areas.Univariate and multivariate survival analyses were performed using a Cox regression model.P<0.05 was considered statistically significant and all P-values were two-sided.RESULTS Among the 204 patients,univariate analysis indicated that macrovascular invasion(MaVI)(P=0.001),microvascular invasion(MVI)(P=0.012),multiple tumors(P=0.008),large tumors(>10 cm)(P=0.001),absence of a tumor capsule(P=0.026),macrotrabecular histological subtype(P=0.001),low density of TILs^(CT)(P=0.039),TILs^(IF)(P=0.014),and PILs(P=0.010)were predictors of progressionfree survival(PFS).Cox multivariate analysis indicated that MaVI(P=0.009),absence of a tumor capsule(P=0.031),low-density of TILs^(IF)(P=0.047)and PILs(P=0.0495)were independent predictors of PFS.A three-category analysis was carried out by combining TILs^(CT),TILs^(IF),and PILs,after which HCCs were classified into immune^(high)[(TILs^(CT))^(high),(TILs^(IF))^(high),and PILs^(high),83 cases],immune^(mod)(tumors other than immune^(high) and immune^(low) subtypes,94 cases),and immune^(low)[(TILs^(CT))^(low),(TILs^(IF))^(low),and PILs^(low),27 cases]subtypes.The immune^(high) subtype had a lower rate of MVI(40.96%)than the immune^(mod)(61.70%,P=0.017)and immune^(low)(66.67%,P=0.020)subtypes.The recurrence rates of the immune^(high),immune^(mod) and immune^(low) subtypes were 10.8%,25.5%and 33.3%,respectively.CONCLUSION HCC patients with high infiltrating lymphocytes tend to have a lower recurrence rate and less MVI.The evaluation of TILs in H&E-stained specimens could be a prognostic parameter for HCC.
基金the National Natural Science Foundation of China (No.39370706).
文摘Objective: To study immunologic character of tumor-infiltrating lymphocytes (TIL) on postin vitro expansion in ovarian carcinoma, and evaluate the prospects by adopting TIL treatment of ovarian carcinoma at an advanced stage. Methods: Cellular phenotype changes in TIL were analyzed by flow cytometry. By means of molecular biology and immunologic methods, ability to secrete cytokines and anti-tumor activities of in TIL was studied. Results: Difference of cellular phenotypes in TIL was probably related to the type, feature and resource of the tumor. TIL obtained from phoroplast and parenchyma was dominant in CD3+CD4+. TIL obtained from tumor tissues, around microvessels and ascitic fluid was dominant in CD3+CD8 Concentration of rIL-2in vitro played a significant role in immunologic character of TIL. By means of rIL-2 expansionin vitro, TIL has apparently been improved in competence of secreting some cytokines, such as IL-2, TNF-α, IFN-γ, and anti-tumor activities. The activated TIL was more stimulated by further adding anti-CD3 or PHA (suitable concentration), which significantly increased its ability to secrete cytokines. Treatment with TIL+CTX or TIL+ rIL-2, could apparently improve phenotypes in peripheral blood of patients, with definitive effects. Conclusion: Immunologic activities of TILin vitro are apparently improved by rIL2 expansion. Regression of tumor, by means of infusion TIL, is not largely attributed to direct cytotoxicity to tumor cells, but indirectly and partly augmenting cellular activities and abilities of immunomodulation in patients with ovarian carcinoma being dependent on secreting multiple cytokines.
文摘Primary tumor tissues in the digestive system were harvested form 15 patients. By mincing,enzymatic digestion and gradient density separation, sufficient TILs(>5×106) were obtained from 13 of 15 (88.7%) patients in vitro in the presence of 500 μ/ml of recombinant interleukin-2 and 5% fetal calf serum after one month culture. 92.3% (12/13) of TILs proliferated well in vitro (92.3%). TILs expanded from 102-folds to 103-folds after being cultured for one month. CD25+ cell of the most fresh TILs was more than that of peripheral blood lymphocytes. CD25+ cells of TILs during 4th week of the culture was significantly greater (P<0.01) than that of fresh TILs. CD4+/CD8+ ratio was decreased during four culture weeks because of increase of CD8 cells. By using modified colorimetric MTT assay for measuring activity of TILs against various tumor cells the results showed that cytotoxicity of gastro-intestinal TILs autologous tumor cells is greater than on the other tumor cells.
文摘Objective: To study the effect of tumor infiltrating lymphocytes at cancer nest on local control of rectal cancer after preoperative radiotherapy. Methods: From Jan. 1999 to Oct. 2007, a total of 107 patients with rectal cancer were reviewed. They were treated by preoperative radiotherapy, 30 Gy/10 fractions/12 days. Two weeks later, the patient underwent a surgical operation. Their pathological samples were kept in our hospital before and after radiotherapy. Lymphocyte infiltration (LI) degree, pathologic degradation and fibrosis degree after radiotherapy in paraffin section were evaluated under microscope. Results: After followed-up of 21 months (2-86 months), a total of 107 patients were reviewed. Univariate analysis showed that lymphocyte infiltration (LI), fibrosis and pathologic changes after radiotherapy were significant factors on local control. Logistic regression analysis showed that LI after radiotherapy was a significant effect factor on local control. Conclusion: LI, fibrosis and pathologic degradation after radiotherapy are significant for local control of rectal cancer after preoperative radiotherapy. LI after radiotherapy was a significantly prognostic index for local control of rectal cancer after preoperative radiotherapy.
基金National Key R&D Program of China,No.2022YFF1203300.
文摘BACKGROUND Tumor budding(TB)has emerged as a promising independent prognostic biomarker in colorectal cancer(CRC).The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC.However,existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies.Consequently,this study investigated the correlation among TB categories,clinicopathological features,and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification.AIM To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC.METHODS The clinical data of 547 CRC patients were collected for this retrospective study.Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines.RESULTS Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy(P=0.004),clinical stage IV(P<0.001),≥4 regional lymph node metastases(P=0.004),left-sided colonic cancer(P=0.040),and Bd 2-3(P=0.002)were independent prognostic factors in patients with stage III-IV CRC.Moreover,the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3,both in the tumor stroma and its invasive margin.CONCLUSION TB has an independent predictive prognostic value in patients with stage III-IV CRC.It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.
基金Supported by Natural Science Foundation of Heilongjiang Province, No.D0234
文摘AIM: To investigate the morphological characterization of tumor infiltrating dendritic cells (TIDCs) and tumor infiltrating lymphocytes (TILs) in human rectal cancer. METHODS: Light and electron microscopy as well as immunohistochemistry were used to observe the distributive and morphological changes of TIDCs and TILs. RESULTS: TIDCs were mainly located in tumor-surrounding tissue. The number of TIDCs in the earlier stage was higher than that in the later stage (P〈 0.01). TILs were mainly seen in adjacent tissue of cancers and tumor-surrounding tissue. There were more TILs in the earlier stage than that in the later stage (P〈0.01). Under electron microscope, TIDCs were irregular in shape and exhibited many dendritic protrusions. It isn't obvious that cancer cells perforated the basement membrane and TILs were arranged along the basement membrane in the earlier stage. In the later stage, it is explicit that cancer cells perforated the basement membrane and surrounded by TILs. There were contacts among TIDCs, TILs and tumor cell. One IIDCs contacted one or several TILs which clustered around TIDCs. Glycogen granules were seen between TIDCs and Tits. CONCLUSION: The number of TIDCs and TILs is related with tumor progression There exist close relationships among TIDCs, TILs and tumor cell.
基金supported by grants from the National Key R & D Program of China (Grant No. 2017YFA0505600-04)National Natural Science Foundation of China (Grant No. 81372887, 81572403, and 81772863)
文摘Objective: To elucidate the role and prognostic significance of lymphocyte activation-gene-3(LAG-3) in soft tissue sarcoma(STS).Methods: The expression of LAG-3 in patient and matched normal blood samples was analyzed by flow cytometry. The localization and prognostic values of LAG-3^+ cells in 163 STS patients were analyzed by immunohistochemistry. In addition, the expression of tumor-infiltrating CD3^+ T, CD4^+ T, and CD8^+ T cells and their role in the prognosis of STS were evaluated by immunohistochemistry. The effect of LAG-3 blockade was evaluated in an immunocompetent MCA205 fibrosarcoma mouse model.Results: Peripheral CD8^+ and CD4^+ T cells from STS patients expressed higher levels of LAG-3 than those from healthy donors.LAG-3 expression in STS was significantly associated with a poor clinical outcome(P = 0.038) and was correlated with high pathological grade(P < 0.001), advanced tumor stage(P = 0.016). Additionally, LAG-3 expression was highly correlated with CD8^+ T-cell infiltration(r = 0.7034, P < 0.001). LAG-3 was expressed in murine tumor-infiltrating lymphocytes, and its blockade decreased tumor growth and enhanced secretion of interferon-gamma by CD8^+ and CD4^+ T cells.Conclusions: LAG-3 blockade may be a promising strategy to improve the effects of targeted therapy in STS.