Cytotoxic T Cells and Granzyme B Associated with Improved Colorectal Cancer Survival in a Prospective Cohort of Older Women

Prizment, Anna E.; Vierkant, Robert A.; Smyrk, Thomas C.; Tillmans, Lori S.; Nelson, Heather H.; Lynch, Charles F.; Pengo, Thomas; Thibodeau, Stephen N.; Church, Timothy R.; Cerhan, James R.; Anderson, Kristin E.; Limburg, Paul J.

doi:10.1158/1055-9965.epi-16-0641

Cited by 52 publications

(51 citation statements)

References 49 publications

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“…This allowed us to identify CD8 þ T-cell granzyme B as a potential effector molecule inhibited by the stromal cell barrier in the tumor microenvironment, which was restored by anti-PD-1 therapy. With specific regard to colon cancer, higher intratumoral expression of granzyme B has been shown to correlate with improved survival in patients (51). Collectively, these data demonstrate the importance of the stromal compartment in modulating the CD8 þ T-cell-mediated antitumor immune responses in a PD-L1-dependent manner.…”

Section: Discussionmentioning

confidence: 74%

Stromal Cell PD-L1 Inhibits CD8+ T-cell Antitumor Immune Responses and Promotes Colon Cancer

O’Malley

Treacy

Lynch

et al. 2018

Cancer Immunology Research

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Stromal cells of mesenchymal origin reside below the epithelial compartment and provide structural support in the intestine. These intestinal stromal cells interact with both the epithelial cell compartments, as well as infiltrating hematopoietic immune cells. The importance of these cells in regulating immune homeostasis during inflammation is well recognized. However, little is known about their function and phenotype in the inflammatory tumor microenvironment. Using a syngeneic, immunogenic model of colorectal cancer, we showed that TNFα-initiated inflammatory signaling in CT26 colorectal cancer cells selectively induced PD-L1 expression in stromal cells. Using shRNA and antibody-mediated approaches, we showed that stromal cell PD-L1 potentiated enhanced immunosuppression, characterized by inhibition of activated CD8 granzyme B-secreting T cells , and the inhibition of CD8 effector cells was associated with enhanced tumor progression. Stromal cell immunosuppressive and tumor-promoting effects could be reversed with administration of anti-PD-1 We validated our findings of stromal cell expression in two cohorts of clinical samples and also observed PD-L1 induction on human stromal cells in response to exposure to the inflammatory secretome from human colon cancer cells, irrespective of microsatellite instability. Collectively, our data showed that tumor-associated stromal cells support T-cell suppression by PD-L1 induction, which is dependent on colon cancer inflammatory signaling. Our findings reveal a key role of mesenchymal stromal cells PD-L1 in suppression of CD8 antitumor immune responses and potentiation of colorectal cancer progression. .

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Section: Discussionmentioning

confidence: 74%

Stromal Cell PD-L1 Inhibits CD8+ T-cell Antitumor Immune Responses and Promotes Colon Cancer

O’Malley

Treacy

Lynch

et al. 2018

Cancer Immunology Research

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“…However, many of these studied overlapping cohorts or assessed more than one marker [21,30,54,[56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75]. In terms of independent cohorts studied in relation to different T-cell markers, there was a total of 63 studies, encompassing 14700 patients [9,13,37,39,. Of the total studies, 67 found a significant positive effect for T-cell infiltration in and around the tumour, but only 47 of these studied independent cohorts, with a total number of 13014 patients [9,13,37,39,76-80,82,83,85,86,89,90,92-95,97-101,103-105, 107-109,112,114,116-119,121-125,127-130,132,133].…”

Section: T-lymphocyte Subsetsmentioning

confidence: 99%

“…In colorectal cancer, there were 44 papers assessing CD8 [13,30,37,39,70,71,[81][82][83]85,86,92,93,98,108,109,112,114,116,117,121,122,125]. Of the nine studies that directly compared intratumoural CD8 assessment: three studies (625 patients) found IE significant where ST was not [75,81,121]; two studies (460 patients) found ST significant where IE was not [83,125]; three studies (1294 patients) found both IE and ST to be significant [71,85,98]; and one (291 patients) study compared IE assessment with combined assessment of IE and ST and found IE alone to be significant [37].…”

Section: Cd8 (Cytotoxic T-cells)mentioning

confidence: 99%

“…However, TMAs may limit the location-specific assessment of prognosis. Similarly, differences in quantification of immune cell density ranging from semiquantitative assessment and manual counts to digital pathology-based assessments and automated cell counting has led to difficulty in standardising a method for clinical implementation [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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The local inflammatory response in colorectal cancer – Type, location or density? A systematic review and meta-analysis

Alexander

McMillan

Park

2020

Cancer Treatment Reviews

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The host anti-tumour inflammatory response is a strong prognostic indicator, and tumour infiltrating lymphocytes (TILs) are believed to have a complimentary role alongside TNM assessment in dictating future management. However, there is wide disagreement regarding the most efficacious and cost-effective method of assessment. Methods: A comprehensive literature search was performed of EMBASE, MedLine and PubMed as well as an assessment of references to identify all relevant studies relating to the assessment of the peri-tumoural inflammatory response or TILs and prognosis in colorectal cancer (CRC). A meta-analysis was performed of 67 studies meeting the REMARK criteria using RevMan software. Results: Intratumoural assessment of both CD3 and CD8 in CRC were significant for disease-free survival (DFS) (combined HRs 0.46; 95%CI: 0.39-0.54 and 0.54; 95%CI: 0.45-0.65), as well as overall survival (OS) and disease-specific survival (DSS). The same was true for assessment of CD3 and CD8 at the invasive margin (DFS: combined HRs 0.45; 95%CI: 0.33-0.61 and 0.51; 95%CI: 0.41-0.62). However, similar fixed effects summaries were also observed for H&E-based methods, like Klintrup-Makinen grade (DFS: HR 0.62; 95%CI: 0.43-0.88). Furthermore, inflammatory assessments were independent of MSI status. Conclusion: The evidence suggests that it is the density of a coordinated local inflammatory infiltrate that confers survival benefit, rather than any individual immune cell subtype. Furthermore, the location of individual cells within the tumour microenvironment does not appear to influence survival. The authors advocate a standardised assessment of the local inflammatory response, but caution against emphasizing the importance of any individual immune cell subtype.

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“…In tumor-in ltrating cytotoxic T lymphocytes, type I interferon is found to inhibit tumor growth by inducing STAT3 activation to promote the expression of GZMB (36). Moreover, Prizment et al has demonstrated that GZMB expression is correlated with the improved survival of patients with colorectal cancer and might be used as a useful prognostic factor (37). In our study, GZMB was a hub node in the two PPI networks constructed by immune-related DEGs of CD4 + and CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Immune‐related Makers Associated with Tumor-infiltrating T Cells in Ovarian Cancer

Liao

Han

Pan

et al. 2020

Preprint

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Background: Tumor-infiltrating T cells in the tumor microenvironment are the biological basis of immunotherapy and promising predictors of cancer prognosis. Aim: The aim of this study was to investigate immune‐related RNAs associated with tumor-infiltrating T cells in ovarian cancer (OV).Methods: The gene expression data of patients with OV were downloaded from The Cancer Genome Atlas (TCGA) database. The immune and stromal scores were calculated and the differentially expressed mRNAs (DEGs) were screened. The abundance of six types of infiltrating immune cells was investigated, and the immune-related DEGs associated with tumor-infiltrating CD4+ and CD8+ T cells were explored by correlation analyses. Subsequently, multiple analyses, i.e., protein-protein interaction (PPI) network analysis, competing endogenous RNA (ceRNA; lncRNA-miRNA-target) network analysis, and small-molecule target network analysis, were performed. Results: In total, 37 and 49 immune-related DEGs of CD4+ and CD8+ T cells were screened, respectively. PPI network results showed that granzyme B (GZMB) was a hub node in the two PPI networks constructed by immune-related DEGs of CD4+ and CD8+ T cells. Moreover, the ceRNA chr22-38_28785274-29006793.1/has-miR-1249-5p/CD3E was obtained from the two constructed ceRNA networks related to CD4+ and CD8+ T cells. Survival analysis revealed that key immune-related DEGs of CD4+ and CD8+ T cells, such as GZMB and CD3E, were positively correlated with patient prognosis. Conclusion: GZMB and ceRNAs, such as chr22-38_28785274-29006793.1/has-miR-1249-5p/CD3E, may mediate the role of tumor-infiltrating T cells in OV. GZMB and CD3E may be used as promising T cell-related biomarkers with prognostic value in OV.

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Cytotoxic T Cells and Granzyme B Associated with Improved Colorectal Cancer Survival in a Prospective Cohort of Older Women

Cited by 52 publications

References 49 publications

Stromal Cell PD-L1 Inhibits CD8+ T-cell Antitumor Immune Responses and Promotes Colon Cancer

Stromal Cell PD-L1 Inhibits CD8+ T-cell Antitumor Immune Responses and Promotes Colon Cancer

The local inflammatory response in colorectal cancer – Type, location or density? A systematic review and meta-analysis

Investigation of Immune‐related Makers Associated with Tumor-infiltrating T Cells in Ovarian Cancer

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