scholarly journals CD8+Foxp3+ tumor infiltrating lymphocytes accumulate in the context of an effective anti-tumor response

2010 ◽  
Vol 129 (3) ◽  
pp. 636-647 ◽  
Author(s):  
Dung T. Le ◽  
Brian H. Ladle ◽  
Timothy Lee ◽  
Vivian Weiss ◽  
Xiaosai Yao ◽  
...  
Keyword(s):  
Tumor Response ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

scholarly journals MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models

2021 ◽  
Vol 22 (17) ◽  
pp. 9168
Author(s):  
Kai-Wen Huang ◽  
Choon Ping Tan ◽  
Vikash Reebye ◽  
Cheng Ean Chee ◽  
Dimitris Zacharoulis ◽  
...  
Keyword(s):  
Tumor Response ◽  
Checkpoint Inhibitor ◽  
Myeloid Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Cancer Model ◽  
Preclinical Models ◽  
Immune Microenvironment ◽  
Clinical Role ◽  
Tumor Immune Microenvironment ◽  
Infiltrating Lymphocytes

The transcription factor CEBPA is a master regulator of liver homeostasis, myeloid cell differentiation and is downregulated in several oncogenic diseases. MTL-CEBPA is a small activating RNA drug which upregulates gene expression of CEBPA for treatment of hepatocellular carcinoma (HCC). We investigate whether MTL-CEBPA has immune modulatory effects by combining MTL-CEBPA with an anti-PD-1 checkpoint inhibitor (CPI) and/or radiofrequency ablation (RFA) in two preclinical models. First, mice with two flanks of HCC tumors (BNL) were treated with combinations of RFA (right flank), anti-PD-1 or MTL-CEBPA. The reduction of the left flank tumors was most pronounced in the group treated with RFA+anti-PD1+MTL-CEBPA and 7/8 animals responded. This was the only group with a significant increase in CD8+ and CD49b+/CD45+ tumor infiltrating lymphocytes (TIL). Second, a combination of anti-PD-1+MTL-CEBPA was tested in a CT26 colon cancer model and this treatment significantly reduced tumor size, modulated the tumor immune microenvironment and increased TILs. These data suggest a clinical role for combination treatment with CPIs, RFA and MTL-CEBPA through synergistic priming of the immune tumor response, enabling RFA and CPIs to have a pronounced anti-tumor effect including activity in non-treated tumors in the case of RFA.

Analysis of Tumor-infiltrating Lymphocytes Following CD45 Enrichment

BIO-PROTOCOL ◽  
2014 ◽  
Vol 4 (16) ◽  
Author(s):  
Rachel Perret ◽  
Sophie Sierro ◽  
Natalia Botelho ◽  
Stephanie Corgnac ◽  
Alena Donda ◽  
...  
Keyword(s):  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

scholarly journals Evaluation of PD-L1 Expression and Associated Tumor-Infiltrating Lymphocytes in Laryngeal Squamous Cell Carcinoma

2015 ◽  
Vol 22 (3) ◽  
pp. 704-713 ◽  
Author(s):  
Maria Vassilakopoulou ◽  
Margaritis Avgeris ◽  
Vamsidhar Velcheti ◽  
Vassiliki Kotoula ◽  
Theodore Rampias ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Laryngeal Squamous Cell Carcinoma ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

scholarly journals 353 Safety and efficacy of tumor infiltrating lymphocytes (TIL, LN-145) in combination with pembrolizumab for advanced, recurrent or metastatic HNSCC

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A378-A378
Author(s):  
Antonio Jimeno ◽  
Sophie Papa ◽  
Missak Haigentz ◽  
Juan Rodríguez-Moreno ◽  
Julian Schardt ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Single Agent ◽  
Objective Response ◽  
Tumor Resection ◽  
Tumor Infiltrating Lymphocytes ◽  
Open Label ◽  
Safety And Efficacy ◽  
Infiltrating Lymphocytes

BackgroundSingle agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored.MethodsIOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naïve HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG <1, at least one resectable metastasis for LN-145 production, and at least another measurable lesion after tumor resection. Primary endpoints are ORR per RECIST v1.1 by investigator and safety as measured by the incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs). LN-145 production method uses central GMP manufacturing in a 22-day process yielding a cryopreserved TIL product (figure 1). Preconditioning chemotherapy consists of cyclophosphamide/fludarabine, followed by LN-145, and then < 6 doses of IL-2 over <3 days. Pembrolizumab is initiated post-tumor harvest but prior to LN-145 and continues after LN-145 infusion Q3W until toxicity or progression (figure 2).ResultsNine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached.Abstract 353 Figure 1Iovance LN-145 (autologous TIL cell therapy product) ManufacturingAbstract 353 Figure 2IOV-COM-202 Study SchemaConclusionsLN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented.Trial RegistrationNCT03645928Ethics ApprovalThe study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

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

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

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

scholarly journals LINC-30. A CLINICOPATHOLOGICAL STUDY OF IMMUNOGENICITY AND IMMUNE EVASION MECHANISMS AMONG MOLECULAR SUBGROUPS OF MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii384-iii384
Author(s):  
Kavneet Kaur ◽  
Vaishali Suri ◽  
Mehar C Sharma ◽  
Ashish Suri ◽  
Chitra Sarkar
Keyword(s):  
Immune Evasion ◽  
Tumor Infiltrating Lymphocytes ◽  
Positive Trend ◽  
Molecular Subgroups ◽  
Methylation Array ◽  
Group 4 ◽  
Prognostic Stratification ◽  
Immune Checkpoint Proteins ◽  
Age Range ◽  
Infiltrating Lymphocytes

Abstract INTRODUCTION Medulloblastomas have been well characterised in terms of genomics, epigenomics, transcriptomics and recently proteomics. However, there is limited knowledge regarding immunogenicity, immune-microenvironment and immune evasion mechanisms in different molecular subgroups of medulloblastoma. It is important to analyze these parameters to understand tumor progression, prognostic stratification as well as treatment response to available immunotherapeutic drugs. MATERIALS AND METHODS Molecular subgrouping performed by immunohistochemistry(IHC), Nanostring and 850k-methylation array. Immune profile by IHC for CD3, 20, CD8 [tumor infiltrating lymphocytes (TILs)], CD163 [tumor-associated macrophages (TAMs)], and PD-L1 and CTLA-4 [immune checkpoint proteins]. RESULTS A total of 35 cases were analyzed with age-range from 1 to 54 years (77% pediatric and 23% adult). 82% cases were located in midline, while rest in cerebellar hemispheres. On molecular subgrouping, MBs were subdivided into 8 WNT, 10 SHH, 8 Group 3 and 9 Group 4. Twenty four cases had follow up, 12 with no evidence of disease while 12 with progressive disease or death. PD-L1 expression ranged from 0% to 20% and included 5SHH, 2WNT and 1Group 3. CTLA4 positive lymphocytes ranged from 0 to 33 in 4 cases: 1WNT, 3 SHH, 1Group4. TILs ranged from 0–220/mm2 with a median of 3. TAMs ranged from 0–60/mm2 with a median of 18. Both TILs and TAMs were significantly higher in SHH subgroup. CONCLUSION PD-L1 positivity and number of TILs and TAMs were significantly more in SHH-subgroup tumors followed by WNT tumors. CTLA-4 expression did not correlate with subgroups. All parameters showed a positive trend with increasing age.

scholarly journals Mismatch repair deficiency is associated with specific morphologic features and frequent loss of ARID1A expression in ovarian clear cell carcinoma

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Huijuan Ge ◽  
Yaoxin Xiao ◽  
Guangqi Qin ◽  
Yanzi Gu ◽  
Xu Cai ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Tumor Infiltrating Lymphocytes ◽  
Tissue Microarrays ◽  
Ovarian Clear Cell Carcinoma ◽  
Repair Deficiency ◽  
Ovarian Epithelial Carcinoma ◽  
Histological Characteristics ◽  
Infiltrating Lymphocytes

Abstract Background Ovarian clear cell carcinoma (OCCC) is the second subtype of ovarian epithelial carcinoma reported to be closely related to Lynch syndrome (LS). ARID1A mutation is an important pathogenetic mechanism in OCCC that leads to loss of ARID1A expression in approximately half of OCCCs. However, the correlation of MMR status and ARID1A deficiency is unclear. The current study aimed to identify the clinical and histopathological characteristics of OCCC associated with dMMR and to further explore the association between dMMR and ARID1A deficiency. Methods A cohort of 176 primary OCCC patients was enrolled and review included histological characteristics (nuclear atypia, necrosis, mitosis, stromal hyalinization, and background precursors) and host inflammatory response (tumor-infiltrating lymphocytes, peritumoral lymphocytes, intratumoral stromal inflammation and plasma cell infiltration). Immunohistochemical staining of MLH1, PMS2, MSH2, MSH6 and ARID1A was performed using tissue microarrays. Results dMMR was detected in 10/176 tumors (6 %), followed by MSH2/MSH6 (6/176), MLH1/PMS2 (3/176), and MSH6 (1/176). The average age of patients with dMMR was younger than that of patients with intact MMR (46 y vs. 53 y). Tumors with diffuse intratumoral stromal inflammation remained significantly associated after multivariate analysis. ARID1A expression was absent in 8 patients with dMMR (8/10), which is a significantly higher frequency than that observed in patients with intact MMR (80 % vs. 43.2 %). Conclusions Our study indicates that diffuse intratumoral stromal inflammation of OCCCs is associated with dMMR, with loss of MSH2/MSH6 expression being most frequent. dMMR is strongly associated with the loss of ARID1A expression in OCCC.

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