Cytolytic Activity Score to Assess Anticancer Immunity in Colorectal Cancer

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d6950545e217">Background:</h5> <p id="P4">Elevated tumor infiltrating lymphocytes (TIL) 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, Cytolytic Activity Score (CAS) would be a useful tool to assess anticancer immunity. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d6950545e222">Methods:</h5> <p id="P5">Genomic expression data was obtained from 456 patients from The Cancer Genome Atlas (TCGA). CAS was defined by GZMA and PRF1 expression. CIBERSORT was used to evaluate intra-tumoral immune cell composition. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d6950545e227">Results:</h5> <p id="P6">High CAS 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. CAS-high CRC patients had improved OS ( <i>p=0.019</i>) and DFS ( <i>p=0.016</i>) compared to CAS-low, especially in TIL-positive tumors. Multivariate analysis demonstrated that CAS-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 (ICM)- PD-1, PD-L1, CTLA4, LAG-3, TIM3 and IDO1 correlated significantly with CAS ( <i>p<0.0001</i>); with improved survival in CAS-high, ICM-low patients and poorer survival in ICM-high patients. </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d6950545e241">Conclusions:</h5> <p id="P7">High CAS within CRC associated with improved survival likely due to increased immunity and cytolytic activity of T cells and M1 macrophages. High CAS also associated with high expression of immune checkpoint molecules, thus further studies to elucidate the role of CAS as a predictive biomarker of the efficacy of immune checkpoint blockade are warranted. </p> </div>

Related collections

Most cited references 28

Record: found
Abstract: found
Article: not found

Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection.

Qiang Gao, Shuang-Jian Qiu, Jia Fan … (2007)

To investigate the prognostic value of tumor-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in hepatocellular carcinoma (HCC) patients after resection. CD3+, CD4+, CD8+, Foxp3-positive, and granzyme B-positive TILs were assessed by immunohistochemistry in tissue microarrays containing HCC from 302 patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff. CD3+, CD4+, CD8+ TILs were associated with neither overall survival (OS) nor disease-free survival (DFS). The presence of low intratumoral Tregs in combination with high intratumoral activated CD8+ cytotoxic cells (CTLs), a balance toward CTLs, was an independent prognostic factor for both improved DFS (P = .001) and OS (P < .0001). Five-year OS and DFS rates were only 24.1% and 19.8% for the group with intratumoral high Tregs and low activated CTLs, compared with 64.0% and 59.4% for the group with intratumoral low Tregs and high activated CTLs, respectively. Either intratumoral Tregs alone (P = .001) or intratumoral activated CTLs (P = .001) alone is also an independent predictor for OS. In addition, high Tregs density was associated with both absence of tumor encapsulation (P = .032) and presence of tumor vascular invasion (P = .031). Tregs are associated with HCC invasiveness, and intratumoral balance of regulatory and cytotoxic T cells is a promising independent predictor for recurrence and survival in HCC. A combination of depletion of Tregs and concomitant stimulation of effector T cells may be an effective immunotherapy to reduce recurrence and prolong survival after surgery.

0 comments Cited 380 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer.

Paul Salama, Michael Phillips, Fabienne Grieu … (2009)

To determine the prognostic significance of FOXP3(+) lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8(+) and CD45RO(+) lymphocyte densities. Tissue microarrays and immunohistochemistry were used to assess the densities of CD8(+), CD45RO(+), and FOXP3(+) lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. FOXP3(+) Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8(+) and CD45RO(+) cell densities were lower. FOXP3(+) Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3(+) Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8(+) and CD45RO(+). High FOXP3(+) Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3(+) Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001). FOXP3(+) Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8(+) and CD45RO(+) lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3(+) Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3(+) Treg density may help to improve the prognostication of early-stage colorectal cancer.

0 comments Cited 366 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer.

Jonna Berntsson, Björn Nodin, Jakob Eberhard … (2016)

Multiple studies have described associations between infiltrating immune cells and prognosis in cancer; however, the clinical relevance has most often been attributed to the T-cell linage. This study aimed to further investigate the clinicopathological correlates and prognostic impact of B cell and plasma cell infiltration in CRC. Immunohistochemical expression of CD20, CD138 and immunoglobulin kappa C (IGKC) was analysed in tissue microarrays with tumours from 557 incident cases of CRC from a prospective population-based cohort. Kaplan-Meier analysis and Cox regression analysis were used to determine the impact of CD20, CD138 and IGKC expression on 5-year overall survival. Immune cell-specific CD20, CD138, and IGKC expression correlated significantly with lower T-stage (p < 0.001, p < 0.001, and p = 0.006, respectively). A higher density of CD20+ cells correlated significantly with an improved OS (HR = 0.53, 95% CI 0.36-0.78), remaining significant in multivariable analysis adjusted for age, TNM stage, differentiation grade and vascular invasion (HR = 0.51; 95% CI 0.33-0.80). Immune cell-specific CD138 and IGKC expression correlated significantly with an improved OS in univariable Cox regression analysis; however, these associations did not remain significant in multivariable analysis. Finally, tumour cell-specific CD138 expression was found to be an independent factor of poor prognosis (HR 1.52; 95% CI 1.03-2.24). The results from the present study demonstrate that B cell infiltration in CRC has a significant impact on tumour progression and prognosis. These findings supplement and extend the current knowledge of the immune landscape in colorectal cancer, and merit further study.