The prognostic significant of tumor budding, tumor stroma ratio and tumor-infiltrating lymphocytes in gallbladder adenocarcinoma

Abstract Purpose To analyze the role of programmed death ligand 1 (PD-L1) immunohistochemisty in the context of tumor microenvironment in colon cancer (CC) with focus on the interaction between tumor budding and tumor-infiltrating lymphocytes (TILs) and to elucidate its potential value for immunooncologic treatment decisions. Methods Three hundred forty seven patients with CC, stages I to IV, were enrolled. PD-L1 immunohistochemistry was performed using two different antibodies (clone 22C3 pharmDx, Agilent and clone QR1, Quartett). Tumor proportion score (TPS) as well as immune cell score (IC) was assessed. Budding and TILs were assessed according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) and International TILs Working Group (ITWG). Correlation analyses as well as survival analyses were performed. Results PD-L1 positivity significantly correlated with TILs > 5% and MMR deficiency, and PD-L1-positive cases (overall and IC) showed significantly longer overall survival (OS) with both antibodies.The parameters “high grade,” “right-sidedness,” and “TILS > 5% regardless of MMR status” evolved as potential parameters for additional immunological treatment decisions. Additionally, TPS positivity correlated with low budding. More PD-L1-positive cases were seen in both high TIL groups. The low budding/high TIL group showed longer disease-free survival and longer OS in PD-L1-positive cases. Conclusion Overall, PD-L1 positivity correlated with markers of good prognosis. PD-L1 immunohistochemistry was able to identify parameters as additional potential candidates for immune therapy. Furthermore, it was able to stratify patients within the low budding/high TIL group with significant prognostic impact.

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Effect of tumor budding and tumor infiltrating lymphocytes on prognosis of colorectal mucinous adenocancers

Medicine Science | International Medical Journal ◽

10.5455/medscience.2019.08.9102 ◽

2019 ◽

Vol 8 (4) ◽

pp. 896

Author(s):

Fatmagul Cabuk ◽

Damlanur Sakiz ◽

Elif Ozer ◽

Zehra Kahraman

Keyword(s):

Tumor Infiltrating Lymphocytes ◽

Tumor Budding ◽

Infiltrating Lymphocytes

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Associations between dynamic-contrast enhanced MRI and tumor infiltrating lymphocytes and tumor-stroma ratio in head and neck squamous cell cancer

Cancer Imaging ◽

10.1186/s40644-021-00429-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Hans-Jonas Meyer ◽

Anne Kathrin Höhn ◽

Alexey Surov

Keyword(s):

Squamous Cell Cancer ◽

Cell Cancer ◽

Tumor Infiltrating Lymphocytes ◽

Tumor Stroma ◽

Vimentin Expression ◽

Dce Mri ◽

Contrast Enhanced ◽

Infiltrating Lymphocytes ◽

Neck Squamous Cell Cancer ◽

Contrast Enhanced Mri

Abstract Objectives The present study used dynamic-contrast enhanced MRI (DCE-MRI) to elucidate possible associations with tumor-infiltrating lymphocytes (TIL), stroma ratio and vimentin expression in head and neck squamous cell cancer (HNSCC). Methods Overall, 26 patients with primary HNSCC of different localizations were involved in the study. DCE-MRI was obtained on a 3 T MRI and analyzed with a whole lesion measurement using a histogram approach. TIL- and vimentin-expression was calculated on bioptic samples before any form of treatment. P16 staining was used to define HPV-status. Results Tumor-stroma ratio correlated with entropy derived from Ktrans (r = − 0.52, p = 0.0071) and with kurtosis derived from Ve (r = − 0.53, p = 0.0058). Several Ve derived parameters correlated with expression of TIL within the stroma compartment. TIL within the tumor compartment correlated with entropy derived from Ktrans (r = 0.39, p = 0.047), p90 derived from Ve (r = 0.41, p = 0.036) and skewness derived from Ve (r = 0.41, p = 0.037). Furthermore, these associations were different between HPV positive and negative tumors. Conclusions DCE-MRI might be able to reflect tumor compartments and TIL expression in HNSCC. The most promising parameters were values derived from Ktrans and Ve.

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S2034 Combined Analysis of Lymph Node Status, Vascular Invasion, Tumor Budding and Tumor Infiltrating Lymphocytes Is Highly Predictive of Local Recurrence in Mismatch Repair-Proficient Colon Cancer

Gastroenterology ◽

10.1016/s0016-5085(08)61404-3 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-301

Author(s):

Inti Zlobec ◽

Kristi Baker ◽

Parham Minoo ◽

Luigi Terracciano ◽

Alessandro Lugli

Keyword(s):

Colon Cancer ◽

Lymph Node ◽

Local Recurrence ◽

Mismatch Repair ◽

Vascular Invasion ◽

Tumor Infiltrating Lymphocytes ◽

Tumor Budding ◽

Lymph Node Status ◽

Combined Analysis ◽

Infiltrating Lymphocytes

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Adjuvant chemotherapy in stage II and III colon cancer: the role of the “budding and TILs-(tumor-infiltrating lymphocytes) combination” as tumor-host antagonists

International Journal of Colorectal Disease ◽

10.1007/s00384-021-03896-9 ◽

2021 ◽

Author(s):

Corinna Lang-Schwarz ◽

Balint Melcher ◽

Theresa Dregelies ◽

Zahra Norouzzadeh ◽

Stefanie Rund-Küffner ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Adjuvant Treatment ◽

Tumor Infiltrating Lymphocytes ◽

Treatment Decisions ◽

Stage Ii ◽

Stage Iii ◽

Tumor Budding ◽

Stage Iii Colon Cancer ◽

Infiltrating Lymphocytes

Abstract Purpose To analyze the influence of adjuvant chemotherapy on the combination of tumor budding and tumor-infiltrating lymphocytes (TILs) in stage II and III colon cancer and to elucidate its potential value for adjuvant treatment decisions. Methods 306 patients with stage II and 205 patients with stage III colon cancer diagnosed between 2005 and 2016 who had undergone surgery in a curative setting were enrolled. Budding and TILs were assessed according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) and the criteria of the International TILs Working Group (ITWG). Combinations of budding and TILs were analyzed, and the influence of adjuvant chemotherapy was assessed. Results In stage II colon cancer, stratification into the four budding/TILs groups showed no significant differences in overall survival (OS) between the chemotherapy and the surgery-alone group, not even in cases with high-risk features. In stage III colon cancer, patients with low budding/high TILs benefited significantly from chemotherapy (p=0.005). Patients with high budding/low TILs as well as high budding/high TILs showed a trend to benefit from adjuvant treatment. However, no chemotherapy benefit was seen for the low budding/low TIL group. Conclusions The budding/TIL combination identified subgroups in stage II and III colon cancer with and without benefit from adjuvant treatment. The results this study suggest that the combination of budding and TILs as tumor-host antagonists might be an additional helpful tool in adjuvant treatment decisions in stage II and III colon cancer.

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Outcome Prediction after Neoadjuvant Chemotherapy (NAC) for Breast Cancer, using Tumor-Infiltrating Lymphocytes within Fibrotic Foci of Tumor Stroma (FF-TILs)

10.21203/rs.3.rs-150877/v1 ◽

2021 ◽

Author(s):

Yuka Asano ◽

Shinichiro Kashiwagi ◽

Rika Kouhashi ◽

Akimichi Yabumoto ◽

Koji Takada ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Multivariable Analysis ◽

Growth Factor Receptor ◽

Disease Free Survival ◽

Tumor Infiltrating Lymphocytes ◽

Tumor Stroma ◽

Hormone Receptor Positive ◽

Close Relationship ◽

Infiltrating Lymphocytes

Abstract Background: Tumor-infiltrating lymphocytes (TILs), which are indicators for monitoring an immune response, are generally mononuclear immunocytes that aggregate with tumors and are thought to have a close relationship with cancer cells. On the other hand, a fibrotic focus (FF) within the stroma of a tumor is a histological formation that plays an important role in the cancer microenvironment with regard to proliferation and development. Here, we focus on TILs that exist within the FF and we have performed pathological evaluations.Methods: Of the 320 patients were treated with neoadjuvant chemotherapy (NAC), 239 subjects who were able to evaluate FF-TILs were targeted. Lymphocytes that infiltrate the FF are FF-TILs.Results: The disease-free survival (DFS) period after NAC for the high-FF-TIL group was found to be significantly longer than that for the low-FF-TIL group for all cases (p < 0.001) and for all subtypes of triple-negative breast cancer (TNBC) (p = 0.001), human epidermal growth factor receptor 2-enriched breast cancer (HER2BC) (p = 0.010), and hormone receptor-positive breast cancer (HRBC) (p = 0.003). In multivariable analysis as well, high-FF-TIL group classification was an independent factor for recurrence after NAC for all cases (p < 0.001, hazard ratio (HR) = 0.198) and all subtypes of TNBC (p = 0.006, HR = 0.172), HER2BC (p = 0.025, HR = 0.135), and HRBC (p = 0.007, HR = 0.228).Conclusions: It is suggested that FF-TILs are a useful factor for predicting recurrence of breast cancer after NAC.Article headings: NAC for breast cancer by evaluation of FF-TILs

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The prognostic and therapeutic implications of distinct patterns of argininosuccinate synthase 1 (ASS1) and arginase-2 (ARG2) expression by cancer cells and tumor stroma in non-small-cell lung cancer

Cancer & Metabolism ◽

10.1186/s40170-021-00264-7 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Alexandra Giatromanolaki ◽

Adrian L. Harris ◽

Michael I. Koukourakis

Keyword(s):

Cancer Cells ◽

Immune Escape ◽

Expression Patterns ◽

Postoperative Outcome ◽

Tumor Infiltrating Lymphocytes ◽

Tumor Stroma ◽

Cancer Cell Growth ◽

Therapeutic Implications ◽

Argininosuccinate Synthase ◽

Infiltrating Lymphocytes

Abstract Background Arginine (Arg) is essential for cancer cell growth and also for the activation of T cells. Thus, therapies aiming to reduce Arg utilization by cancer may prove detrimental for the immune response. Methods We examined the expression of two major enzymes involved in arginine depletion and replenishment, namely arginase ARG2 and argininosuccinate synthase ASS1, respectively, in a series of 98 NSCLCs. Their association with immune infiltrates and the postoperative outcome were also studied. Results ARG2 was expressed mainly by cancer-associated fibroblasts (CAFs) (58/98 cases; 59.2%), while ASS1 by cancer cells (75/98 cases; 76.5%). ASS1 and ARG2 expression patterns were not related to hypoxia markers. Auxotrophy, implied by the lack of expression of ASS1 in cancer cells, was associated with high angiogenesis (p < 0.02). ASS1 expression by cancer cells was associated with a high density of iNOS-expressing tumor-infiltrating lymphocytes (iNOS+TILs). ARG2 expression by CAFs was inversely related to the TIL-density and linked with poorer prognosis (p = 0.02). Patients with ASS1 expression by cancer cells had a better prognosis especially when CAFs did not express ARG2 (p = 0.004). Conclusions ARG2 and ASS1 enzymes are extensively expressed in NSCLC stroma and cancer cells, respectively. Auxotrophic tumors have a poor prognosis, potentially by utilizing Arg, thus reducing Arg-dependent TIL anti-tumor activity. ASS1 expression in cancer cells would allow Arg fueling of iNOS+TILs and enhance anti-tumor immunity. However, upregulation of ARG2 in CAFs may divert Arg from TILs, allowing immune escape. Identification of these three distinct phenotypes may be useful in the individualization of Arg-targeting therapies and immunotherapy.

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Viagenpumatucel-L (HS-110) plus nivolumab in patients with advanced non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.8_suppl.101 ◽

2019 ◽

Vol 37 (8_suppl) ◽

pp. 101-101

Author(s):

Daniel Morgensztern ◽

Lyudmila Bazhenova ◽

Saiama Naheed Waqar ◽

Lori McDermott ◽

Jeff Hutchins ◽

...

Keyword(s):

Tumor Progression ◽

Objective Response ◽

Progression Free Survival ◽

Tumor Infiltrating Lymphocytes ◽

Tumor Stroma ◽

Free Survival ◽

Grade 5 ◽

Previously Treated ◽

Infiltrating Lymphocytes

101 Background: Viagenpumatucel-L (HS-110) is an allogeneic cellular vaccine derived from a human lung adenocarcinoma (AD) cell line transfected with the gp96-Ig fusion protein. DURGA is a multi-cohort study evaluating the combination of HS-110 and immune checkpoint blockers (ICBs) in patients with advanced NSCLC. Here we report the initial two cohorts with the combination of HS-110 and nivolumab. Methods: Patients (pts) with previously treated NSCLC received 1 X 107 HS-110 cells weekly for the first 18 weeks and nivolumab 3 mg/kg or 240 mg every 2 weeks until intolerable toxicity or tumor progression. Tissue was tested at baseline for PD-L1 expression (≥ 1% or < 1%) and tumor infiltrating lymphocytes (TILs). TIL high was defined by more than 10% CD8+ lymphocytes in the tumor stroma. Pts in cohort A had never received, and pts in cohort B had received, prior ICBs. The primary objectives were safety and objective response rates (ORR). Results: As of the August 2018 data cut-off, there were 43 pts enrolled into cohort A (40 AD and 3 squamous cell carcinoma [SCC]) and 18 pts in cohort B (15 AD and 3 SCC). In cohort A, 14 pts (32.6%) were TIL high, 13 (30.2%) TIL low and 16 (37.2%) TIL unknown. ORR, disease control rate (DCR), median progression-free survival (PFS) and 1 year PFS were 18.6%, 48.8%, 1.9 months and 23.9% respectively in cohort A, with median follow up of 432 days. ORR, DCR, and PFS were 22%, 50% and 2.2 months respectively in cohort B, with median follow up of 43 days. The median overall survival (mOS) was not reached in either cohort. In cohort A, TIL low at baseline was associated with increased mOS compared to TIL high (not reached vs 13.8 months, hazard ratio [HR] 0.23, 95% CI 0.068-0.81, p = 0.04). There were no differences in mOS according to PD-L1 status in cohort A (p = 0.82). 57 (93%) pts experienced at least one adverse event (AE), of which 39 (64%) were grade 1 or 2. The most common AEs were fatigue (31%), cough and diarrhea (19.7% each). There were 2 grade 5 AEs (3.3%) caused by pulmonary embolism and tumor progression, neither considered to be treatment related. Conclusions: The combination of HS-110 and nivolumab is safe with encouraging preliminary efficacy data. The study is ongoing and additional populations are being explored. Clinical trial information: NCT02439450.

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