Skip to main content
Erschienen in: Annals of Surgical Oncology 8/2018

16.05.2018 | Colorectal Cancer

Cytolytic Activity Score to Assess Anticancer Immunity in Colorectal Cancer

verfasst von: Sumana Narayanan, MD, Tsutomu Kawaguchi, MD, PhD, Li Yan, PhD, Xuan Peng, MS, Qianya Qi, MS, Kazuaki Takabe, MD, PhD, FACS

Erschienen in: Annals of Surgical Oncology | Ausgabe 8/2018

Einloggen, um Zugang zu erhalten

Abstract

Background

Elevated tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment is a known positive prognostic factor in colorectal cancer (CRC). We hypothesized that since cytotoxic T cells release cytolytic proteins such as perforin (PRF1) and pro-apoptotic granzymes (GZMA) to attack cancer cells, a cytolytic activity score (CYT) would be a useful tool to assess anticancer immunity.

Methods

Genomic expression data were obtained from 456 patients from The Cancer Genome Atlas (TCGA). CYT was defined by GZMA and PRF1 expression, and CIBERSORT was used to evaluate intratumoral immune cell composition.

Results

High CYT was associated with high microsatellite instability (MSI-H), as well as high levels of activated memory CD4+T cells, gamma-delta T cells, and M1 macrophages. CYT-high CRC patients had improved overall survival (p = 0.019) and disease-free survival (p = 0.016) compared with CYT-low CRC patients, especially in TIL-positive tumors. Multivariate analysis demonstrated that CYT- high associates with improved survival independently after controlling for age, lymphovascular invasion, colonic location, microsatellite instability, and TIL positivity. The levels of immune checkpoint molecules (ICMs)—programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), T cell immunoglobulin and mucin domain 3 (TIM3), and indoleamine 2,3-dioxygenase 1 (IDO1)—correlated significantly with CYT (p < 0.0001); with improved survival in CYT-high and ICM-low patients, and poorer survival in ICM-high patients.

Conclusions

High CYT within CRC is associated with improved survival, likely due to increased immunity and cytolytic activity of T cells and M1 macrophages. High CYT is also associated with high expression of ICMs; thus, further studies to elucidate the role of CYT as a predictive biomarker of the efficacy of immune checkpoint blockade are warranted.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Li P, Xiao Z, et al. A relationship to survival is seen by combining the factors of mismatch repair status, tumor location and age of onset in colorectal cancer patients. PLoS ONE 2017; 12:e0172799.CrossRefPubMedPubMedCentral Li P, Xiao Z, et al. A relationship to survival is seen by combining the factors of mismatch repair status, tumor location and age of onset in colorectal cancer patients. PLoS ONE 2017; 12:e0172799.CrossRefPubMedPubMedCentral
2.
Zurück zum Zitat Marmol I, Sanchez-de-Diego C, et al. Colorectal carcinoma: a general overview and future perspectives in colorectal cancer. Int J Mol Sci. 2017;18(1):197.CrossRefPubMedCentral Marmol I, Sanchez-de-Diego C, et al. Colorectal carcinoma: a general overview and future perspectives in colorectal cancer. Int J Mol Sci. 2017;18(1):197.CrossRefPubMedCentral
3.
4.
Zurück zum Zitat Green AR, Aleskandarany MA, et al. Clinical impact of tumor DNA repair expression and T-cell infiltration in breast cancers. Cancer Immunol Res 2017; 5:292–99.CrossRefPubMed Green AR, Aleskandarany MA, et al. Clinical impact of tumor DNA repair expression and T-cell infiltration in breast cancers. Cancer Immunol Res 2017; 5:292–99.CrossRefPubMed
5.
Zurück zum Zitat Park JH, Powell AG, et al. Mismatch repair status in patients with primary operable colorectal cancer: associations with the local and systemic tumour environment. Br J Cancer 2016; 114:562–70.CrossRefPubMedPubMedCentral Park JH, Powell AG, et al. Mismatch repair status in patients with primary operable colorectal cancer: associations with the local and systemic tumour environment. Br J Cancer 2016; 114:562–70.CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat Prall F, Huhns M. The PD-1 expressing immune phenotype of T cell exhaustion is prominent in the ‘immunoreactive’ microenvironment of colorectal carcinoma. Histopathology 2017; 71:366–74.CrossRefPubMed Prall F, Huhns M. The PD-1 expressing immune phenotype of T cell exhaustion is prominent in the ‘immunoreactive’ microenvironment of colorectal carcinoma. Histopathology 2017; 71:366–74.CrossRefPubMed
7.
Zurück zum Zitat Salama P, Phillips M, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009; 27:186–92.CrossRefPubMed Salama P, Phillips M, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009; 27:186–92.CrossRefPubMed
8.
Zurück zum Zitat Governa V, Trella E, et al. The interplay between neutrophils and CD8(+) T cells improves survival in human colorectal cancer. Clin Cancer Res 2017; 23:3847–58.CrossRefPubMed Governa V, Trella E, et al. The interplay between neutrophils and CD8(+) T cells improves survival in human colorectal cancer. Clin Cancer Res 2017; 23:3847–58.CrossRefPubMed
9.
Zurück zum Zitat Daster S, Eppenberger-Castori S, et al. High frequency of CD8 positive lymphocyte infiltration correlates with lack of lymph node involvement in early rectal cancer. Dis Markers 2014; 2014:792183.CrossRefPubMedPubMedCentral Daster S, Eppenberger-Castori S, et al. High frequency of CD8 positive lymphocyte infiltration correlates with lack of lymph node involvement in early rectal cancer. Dis Markers 2014; 2014:792183.CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Berntsson J, Nodin B, et al. Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer. Int J Cancer 2016; 139:1129–39.CrossRefPubMed Berntsson J, Nodin B, et al. Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer. Int J Cancer 2016; 139:1129–39.CrossRefPubMed
11.
Zurück zum Zitat Woodsworth DJ, Dreolini L, et al. Targeted cell-to-cell delivery of protein payloads via the granzyme-perforin pathway. Mol Ther Methods Clin Dev 2017; 7:132–45.CrossRefPubMedPubMedCentral Woodsworth DJ, Dreolini L, et al. Targeted cell-to-cell delivery of protein payloads via the granzyme-perforin pathway. Mol Ther Methods Clin Dev 2017; 7:132–45.CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Balli D, Rech AJ, et al. Immune cytolytic activity stratifies molecular subsets of human pancreatic cancer. Clin Cancer Res 2017; 23:3129–38.CrossRefPubMed Balli D, Rech AJ, et al. Immune cytolytic activity stratifies molecular subsets of human pancreatic cancer. Clin Cancer Res 2017; 23:3129–38.CrossRefPubMed
13.
14.
Zurück zum Zitat Colaprico A, Silva TC, et al. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res 2016; 44:e71.CrossRefPubMed Colaprico A, Silva TC, et al. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res 2016; 44:e71.CrossRefPubMed
15.
Zurück zum Zitat Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490:61–70.CrossRef Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490:61–70.CrossRef
16.
Zurück zum Zitat Cancer Genome Atlas Research Network, Weinstein JN, et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet 2013; 45:1113–20.CrossRef Cancer Genome Atlas Research Network, Weinstein JN, et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet 2013; 45:1113–20.CrossRef
17.
Zurück zum Zitat Crowley J, Le Blan M, Jacobson J, Salmon S. Some exploratory tools for survival analysis. Lecture Notes on Statistics. In: Proceedings of the First Seattle Symposium in Biostatistics: Survival Analysis. New York: Springer; 1997. pp. 199–229. Crowley J, Le Blan M, Jacobson J, Salmon S. Some exploratory tools for survival analysis. Lecture Notes on Statistics. In: Proceedings of the First Seattle Symposium in Biostatistics: Survival Analysis. New York: Springer; 1997. pp. 199–229.
19.
Zurück zum Zitat Hause RJ, Pritchard CC, et al. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med 2016; 22:1342–50.CrossRefPubMed Hause RJ, Pritchard CC, et al. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med 2016; 22:1342–50.CrossRefPubMed
20.
Zurück zum Zitat Ramanathan R, Olex AL, et al. Angiopoietin pathway gene expression associated with poor breast cancer survival. Breast Cancer Res Treat 2017; 162:191–98.CrossRefPubMedPubMedCentral Ramanathan R, Olex AL, et al. Angiopoietin pathway gene expression associated with poor breast cancer survival. Breast Cancer Res Treat 2017; 162:191–98.CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Young J, Kawaguchi T, et al. Tamoxifen sensitivity-related microRNA-342 is a useful biomarker for breast cancer survival. Oncotarget 2017; 8:99978–89.PubMedPubMedCentral Young J, Kawaguchi T, et al. Tamoxifen sensitivity-related microRNA-342 is a useful biomarker for breast cancer survival. Oncotarget 2017; 8:99978–89.PubMedPubMedCentral
22.
Zurück zum Zitat Kawaguchi T, Yan L, et al. Overexpression of suppressive microRNAs, miR-30a and miR-200c are associated with improved survival of breast cancer patients. Sci Rep 2017; 7:15945.CrossRefPubMedPubMedCentral Kawaguchi T, Yan L, et al. Overexpression of suppressive microRNAs, miR-30a and miR-200c are associated with improved survival of breast cancer patients. Sci Rep 2017; 7:15945.CrossRefPubMedPubMedCentral
23.
Zurück zum Zitat Kim SY, Kawaguchi T, et al. Clinical relevance of microRNA expressions in breast cancer validated using the cancer genome atlas (TCGA). Ann Surg Oncol 2017; 24:2943–49.CrossRefPubMedPubMedCentral Kim SY, Kawaguchi T, et al. Clinical relevance of microRNA expressions in breast cancer validated using the cancer genome atlas (TCGA). Ann Surg Oncol 2017; 24:2943–49.CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Markl B, Wieberneit J, et al. Number of intratumoral T lymphocytes is associated with lymph node size, lymph node harvest, and outcome in node-negative colon cancer. Am J Clin Pathol 2016; 145:826–36.CrossRefPubMed Markl B, Wieberneit J, et al. Number of intratumoral T lymphocytes is associated with lymph node size, lymph node harvest, and outcome in node-negative colon cancer. Am J Clin Pathol 2016; 145:826–36.CrossRefPubMed
29.
Zurück zum Zitat Yan H, Zhang P, et al. Primary Tr1 cells from metastatic melanoma eliminate tumor-promoting macrophages through granzyme B- and perforin-dependent mechanisms. Tumour Biol 2017; 39:1010428317697554.PubMed Yan H, Zhang P, et al. Primary Tr1 cells from metastatic melanoma eliminate tumor-promoting macrophages through granzyme B- and perforin-dependent mechanisms. Tumour Biol 2017; 39:1010428317697554.PubMed
30.
Zurück zum Zitat Kiladjian JJ, Visentin G, et al. Activation of cytotoxic T-cell receptor gammadelta T lymphocytes in response to specific stimulation in myelodysplastic syndromes. Haematologica 2008; 93:381–89.CrossRefPubMed Kiladjian JJ, Visentin G, et al. Activation of cytotoxic T-cell receptor gammadelta T lymphocytes in response to specific stimulation in myelodysplastic syndromes. Haematologica 2008; 93:381–89.CrossRefPubMed
31.
Zurück zum Zitat Burmeister K, Quagliata L, et al. Vascular endothelial growth factor A amplification in colorectal cancer is associated with reduced M1 and M2 macrophages and diminished PD-1-expressing lymphocytes. PLoS ONE 2017; 12:e0175563.CrossRefPubMedPubMedCentral Burmeister K, Quagliata L, et al. Vascular endothelial growth factor A amplification in colorectal cancer is associated with reduced M1 and M2 macrophages and diminished PD-1-expressing lymphocytes. PLoS ONE 2017; 12:e0175563.CrossRefPubMedPubMedCentral
32.
Zurück zum Zitat Holder KA, Comeau EM, et al. Origins of natural killer cell memory: special creation or adaptive evolution. Immunology 2018;154:38–49.CrossRefPubMed Holder KA, Comeau EM, et al. Origins of natural killer cell memory: special creation or adaptive evolution. Immunology 2018;154:38–49.CrossRefPubMed
33.
Zurück zum Zitat Lee LH, Cavalcanti MS, et al. Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma. Mod Pathol 2016; 29:1433–42.CrossRefPubMedPubMedCentral Lee LH, Cavalcanti MS, et al. Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma. Mod Pathol 2016; 29:1433–42.CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat Toh JW, de Souza P, et al. The potential value of immunotherapy in colorectal cancers: review of the evidence for programmed death-1 inhibitor therapy. Clin Colorectal Cancer 2016; 15:285–91.CrossRefPubMed Toh JW, de Souza P, et al. The potential value of immunotherapy in colorectal cancers: review of the evidence for programmed death-1 inhibitor therapy. Clin Colorectal Cancer 2016; 15:285–91.CrossRefPubMed
36.
Zurück zum Zitat Prado-Garcia H, Romero-Garcia S, et al. The PD-L1/PD-1 pathway promotes dysfunction, but not “exhaustion”, in tumor-responding T cells from pleural effusions in lung cancer patients. Cancer Immunol Immunother 2017; 66:765–76.CrossRefPubMed Prado-Garcia H, Romero-Garcia S, et al. The PD-L1/PD-1 pathway promotes dysfunction, but not “exhaustion”, in tumor-responding T cells from pleural effusions in lung cancer patients. Cancer Immunol Immunother 2017; 66:765–76.CrossRefPubMed
37.
Zurück zum Zitat Schreiber RD, Old LJ, et al. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011; 331:1565–70.CrossRefPubMed Schreiber RD, Old LJ, et al. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011; 331:1565–70.CrossRefPubMed
38.
Zurück zum Zitat Ali HR, Chlon L, et al. Patterns of immune infiltration in breast cancer and their clinical implications: a gene-expression-based retrospective study. PLoS Med 2016; 13:e1002194.CrossRefPubMedPubMedCentral Ali HR, Chlon L, et al. Patterns of immune infiltration in breast cancer and their clinical implications: a gene-expression-based retrospective study. PLoS Med 2016; 13:e1002194.CrossRefPubMedPubMedCentral
39.
Zurück zum Zitat Katz SC, Bamboat ZM, et al. Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol 2013; 20:946–55.CrossRefPubMed Katz SC, Bamboat ZM, et al. Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol 2013; 20:946–55.CrossRefPubMed
40.
Zurück zum Zitat Saigusa S, Toiyama Y, et al. Implication of programmed cell death ligand 1 expression in tumor recurrence and prognosis in rectal cancer with neoadjuvant chemoradiotherapy. Int J Clin Oncol 2016; 21:946–52.CrossRefPubMed Saigusa S, Toiyama Y, et al. Implication of programmed cell death ligand 1 expression in tumor recurrence and prognosis in rectal cancer with neoadjuvant chemoradiotherapy. Int J Clin Oncol 2016; 21:946–52.CrossRefPubMed
41.
Zurück zum Zitat Gao Q, Qiu SJ, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25:2586–93.CrossRefPubMed Gao Q, Qiu SJ, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25:2586–93.CrossRefPubMed
42.
Zurück zum Zitat Anderson AC. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res 2014; 2:393–98.CrossRefPubMed Anderson AC. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res 2014; 2:393–98.CrossRefPubMed
43.
Metadaten
Titel
Cytolytic Activity Score to Assess Anticancer Immunity in Colorectal Cancer
verfasst von
Sumana Narayanan, MD
Tsutomu Kawaguchi, MD, PhD
Li Yan, PhD
Xuan Peng, MS
Qianya Qi, MS
Kazuaki Takabe, MD, PhD, FACS
Publikationsdatum
16.05.2018
Verlag
Springer International Publishing
Erschienen in
Annals of Surgical Oncology / Ausgabe 8/2018
Print ISSN: 1068-9265
Elektronische ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-018-6506-6

Weitere Artikel der Ausgabe 8/2018

Annals of Surgical Oncology 8/2018 Zur Ausgabe

Update Chirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

S3-Leitlinie „Diagnostik und Therapie des Karpaltunnelsyndroms“

CME: 2 Punkte

Prof. Dr. med. Gregor Antoniadis Das Karpaltunnelsyndrom ist die häufigste Kompressionsneuropathie peripherer Nerven. Obwohl die Anamnese mit dem nächtlichen Einschlafen der Hand (Brachialgia parästhetica nocturna) sehr typisch ist, ist eine klinisch-neurologische Untersuchung und Elektroneurografie in manchen Fällen auch eine Neurosonografie erforderlich. Im Anfangsstadium sind konservative Maßnahmen (Handgelenksschiene, Ergotherapie) empfehlenswert. Bei nicht Ansprechen der konservativen Therapie oder Auftreten von neurologischen Ausfällen ist eine Dekompression des N. medianus am Karpaltunnel indiziert.

Prof. Dr. med. Gregor Antoniadis
Berufsverband der Deutschen Chirurgie e.V.

S2e-Leitlinie „Distale Radiusfraktur“

CME: 2 Punkte

Dr. med. Benjamin Meyknecht, PD Dr. med. Oliver Pieske Das Webinar S2e-Leitlinie „Distale Radiusfraktur“ beschäftigt sich mit Fragen und Antworten zu Diagnostik und Klassifikation sowie Möglichkeiten des Ausschlusses von Zusatzverletzungen. Die Referenten erläutern, welche Frakturen konservativ behandelt werden können und wie. Das Webinar beantwortet die Frage nach aktuellen operativen Therapiekonzepten: Welcher Zugang, welches Osteosynthesematerial? Auf was muss bei der Nachbehandlung der distalen Radiusfraktur geachtet werden?

PD Dr. med. Oliver Pieske
Dr. med. Benjamin Meyknecht
Berufsverband der Deutschen Chirurgie e.V.

S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“

CME: 2 Punkte

Dr. med. Mihailo Andric
Inhalte des Webinars zur S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“ sind die Darstellung des Projektes und des Erstellungswegs zur S1-Leitlinie, die Erläuterung der klinischen Relevanz der Klassifikation EAES 2015, die wissenschaftliche Begründung der wichtigsten Empfehlungen und die Darstellung stadiengerechter Therapieoptionen.

Dr. med. Mihailo Andric
Berufsverband der Deutschen Chirurgie e.V.