scholarly journals Prognostic significance of CD8+ T-cells density in stage III colorectal cancer depends on SDF-1 expression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexandros Lalos ◽  
Ali Tülek ◽  
Nadia Tosti ◽  
Robert Mechera ◽  
Alexander Wilhelm ◽  
...  

AbstractSince colorectal cancer (CRC) remains one of the most common malignancies, a tremendous amount of studies keep taking place in this field. Over the past 25 years, a notable part of the scientific community has focused on the association between the immune system and colorectal cancer. A variety of studies have shown that high densities of infiltrating CD8+ T-cells are associated with improved disease-free and overall survival in CRC. Stromal cell-derived factor-1 (SDF-1) is a protein that regulates leukocyte trafficking and is variably expressed in several healthy and malignant tissues. There is strong evidence that SDF-1 has a negative prognostic impact on a variety of solid tumors. However, the existing data do not provide sufficient evidence that the expression of SDF-1 has an influence on CRC. Knowing nowadays, that the microenvironment plays a crucial role in the development of cancer, we hypothesized that the expression of SDF-1 in CRC could influence the prognostic significance of CD8+ T-cells, as an indicator of the essential role of the immune microenvironment in cancer development. Therefore, we explored the combined prognostic significance of CD8+ T-cell density and SDF-1 expression in a large CRC collective. We analyzed a tissue microarray of 613 patient specimens of primary CRCs by immunohistochemistry (IHC) for the CD8 + T-cells density and the expression of SDF-1 by tumor cells and tumor-infiltrating immune cells. Besides, we analyzed the expression of SDF-1 at the RNA level in The Cancer Genome Atlas cohort. We found that the combined high CD8+ T-cell infiltration and expression of SDF-1 shows a favorable 5-year overall survival rate (66%; 95% CI 48–79%) compared to tumors showing a high expression of CD8+ T-cell only (55%; 95% CI 45–64%; p = 0.0004). After stratifying the patients in nodal negative and positive groups, we found that the prognostic significance of CD8+ T-cell density in nodal positive colorectal cancer depends on SDF-1 expression. Univariate and multivariate Hazard Cox regression survival analysis considering the combination of both markers revealed that the combined high expression of SDF-1 and CD8+ T-cell density was an independent, favorable, prognostic marker for overall survival (HR = 0.34, 95% CI 0.17–0.66; p = 0.002 and HR = 0.45, 95% CI 0.23–0.89; p = 0.021, respectively). In our cohort there was a very weak correlation between SDF-1 and CD8+ T-cells (rs = 0.13, p = 0.002) and in the trascriptomic expression of these two immune markers display a weak correlation (rs = 0.28, p < 0.001) which was significantly more pronounced in stage III cancers (rs = 0.40, p < 0.001). The combination of high CD8+ T-cell density and expression of SDF-1 represents an independent, favorable, prognostic condition in CRC, mostly in patients with stage III disease.

2020 ◽  
Author(s):  
Alexandros Lalos ◽  
Ali Tülek ◽  
Nadia Tosti ◽  
Robert Mechera ◽  
Alexander Wilhelm ◽  
...  

Abstract Background: Since colorectal cancer (CRC) remains one of the most common malignancies, a tremendous amount of studies keep taking place in this field. Over the past 25 years, a notable part of the scientific community has focused on the association between the immune system and colorectal cancer. A variety of studies have shown that high densities of infiltrating CD8+ T cells are associated with improved disease-free and overall survival in colorectal cancer (CRC). Stromal cell-derived factor-1 (SDF-1) is a protein that regulates leukocyte trafficking and is variably expressed in several healthy and malignant tissues. There is strong evidence that SDF-1 has a negative prognostic impact on colorectal cancer (CRC). However, based on a significant correlation of SDF-1 and CD8+ T cells in a previous study (r=0.53, p<0.0001), we hypothesized that the prognostic significance of SDF-1 in CRC could depend on the immune microenvironment. Therefore, we explored the combined prognostic significance of SDF-1 expression and CD8+ T cell density in a large CRC collective. Methods: We analyzed a tissue microarray (TMA) of 613 patient specimens of primary CRCs by immunohistochemistry (IHC) for the expression of SDF-1 by tumor cells and tumor-infiltrating immune cells (TICs) and CD8+ T-cells. Besides, we analyzed the expression of SDF-1 at the RNA level in The Cancer Genome Atlas cohort (TCGA). Results: We found that the the combined high expression of SDF-1 and CD8+ T-cell infiltration shows a favorable 5-year overall survival rate (66%; 95%CI=48–79%) compared to tumors showing a high expression of CD8+ T-cells only (55%; 95%CI=45–64%; p=0.0004). High expression of SDF-1 and CD8+ T-cells infiltration was significantly associated with a favorable prognosis also in a validation group (p=0.016). Univariate and multivariate Hazard Cox regression survival analysis considering the combination of both markers revealed that the combined high expression of SDF-1 and CD8+ T cells was an independent, favorable, prognostic marker for overall survival (HR=0.34, 95%CI=0.17–0.66; p=0.002 and HR=0.45, 95%CI=0.23–0.89; p=0.021, respectively). In a spearman’s correlation analysis from the TCGA cohort, SDF-1 also correlated significantly with CD8+ T cells (r=0.28). Conclusions: SDF-1 high /CD8 high density represents an independent, favorable, prognostic condition in CRC, most likely due to an effective antigen-specific immune response.


2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Weixia Wang ◽  
Hongyan Jing ◽  
Jican Liu ◽  
Dacheng Bu ◽  
Yingyi Zhang ◽  
...  

Abstract Background The effect of schistosomiasis on CD8+ T cells and then on PD-L1 expression was unknown, and the utility of CD8+ TILs as a biomarker for schistosomal-associated colorectal cancer (SCRC) rarely has been reported. Methods Three hundred thirty-eight patients with colorectal cancer (CRC) were enrolled. Immunohistochemical analysis was conducted to evaluate the expression of PD-L1 and the infiltration of CD8+ T cells. Results In the total cohort, the results showed that CD8+ TIL density was positively correlated with tumoral (p = 0.0001) and stromal PD-L1 expression (p = 0.0102). But there were no correlation between schistosomiasis and CD8+ TILs and PD-L1. Furthermore, CD8+ TIL density (p = 0.010), schistosomiasis (p = 0.042) were independent predictive factors for overall survival (OS). Stromal PD-L1 (sPD-L1) was correlated with OS (p = 0.046), but it was not an independent predictor. In patients without schistosomiasis, CD8 + T cells (p = 0.002) and sPD-L1 (p = 0.005) were associated with better OS. In patients with schistosomiasis, CD8 + T cells were independent prognosis factor (p = 0.045). Conclusions The study showed that CD8+ TILs was an independent predictive factor for OS in CRC and SCRC patients. The expression of PD-L1 was positively associated with CD8 + TILs density. There were no correlation between schistosomiasis and CD8 + TILs and PD-L1. Stromal PD-L1 but not tPD-L1 was significantly associated with OS, whereas it was not an independent prognostic factor.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3378
Author(s):  
Ileana S. Mauldin ◽  
Jasmin Jo ◽  
Nolan A. Wages ◽  
Lalanthica V. Yogendran ◽  
Adela Mahmutovic ◽  
...  

Background: tumor-infiltrating lymphocytes are prognostic in many human cancers. However, the prognostic value of lymphocytes infiltrating glioblastoma (GBM), and roles in tumor control or progression are unclear. We hypothesized that B and T cell density, and markers of their activity, proliferation, differentiation, or function, would have favorable prognostic significance for patients with GBM. Methods: initial resection specimens from 77 patients with IDH1/2 wild type GBM who received standard-of-care treatment were evaluated with multiplex immunofluorescence histology (mIFH), for the distribution, density, differentiation, and proliferation of T cells and B cells, as well as for the presence of tertiary lymphoid structures (TLS), and IFNγ expression. Immune infiltrates were evaluated for associations with overall survival (OS) by univariate and multivariate Cox proportional hazards modeling. Results: in univariate analyses, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.36, p = 0.001) and CD20+ cells (HR 0.51, p = 0.008), as well as CD8+Tbet+ cells (HR 0.46, p = 0.004), and RORγt+ cells (HR 0.56, p = 0.04). Conversely, IFNγ intensity was associated with diminished OS (HR 0.59, p = 0.036). In multivariable analyses, adjusting for clinical variables, including age, resection extent, Karnofsky Performance Status (KPS), and MGMT methylation status, improved OS was associated with high densities of proliferating (Ki67+) CD8+ cells (HR 0.15, p < 0.001), and higher ratios of CD8+ cells to CD4+ cells (HR 0.31, p = 0.005). Diminished OS was associated with increases in patient age (HR 1.21, p = 0.005) and higher mean intensities of IFNγ (HR 2.13, p = 0.027). Conclusions: intratumoral densities of proliferating CD8 T cells and higher CD8/CD4 ratios are independent predictors of OS in patients with GBM. Paradoxically, higher mean intensities of IFNγ in the tumors were associated with shorter OS. These findings suggest that survival may be enhanced by increasing proliferation of tumor-reactive CD8+ T cells and that approaches may be needed to promote CD8+ T cell dominance in GBM, and to interfere with the immunoregulatory effects of IFNγ in the tumor microenvironment.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10038-10038
Author(s):  
Maarten Slagter ◽  
Elisa A. Rozeman ◽  
Huiwen Ding ◽  
Judith M. Versluis ◽  
Mesele Valenti ◽  
...  

10038 Background: Only a subset of advanced melanoma patients respond to anti-PD-1 (aPD1) monotherapy. Upfront identification of (non-)responsiveness would help guide first-line treatment decisions, prevent overtreatment and unnecessary risk for toxicities. T cell density and expression of T cell related genes have been associated with response to aPD1, but are imperfect predictors. We investigated whether spatial proximity of CD8 T cells to tumor cells improves upon the predictive value of T cell density alone. Methods: Pretreatment tumor specimens from melanoma patients treated with aPD1 in the Netherlands Cancer Institute were stained for DAPI, SOX10/Melan-A, CD4, CD8, FOXP3 and PD-1 by multiplex immunofluorescence. Sections were imaged on Vectra and analyzed using HALO to optimize marker thresholds and demarcate tumor and stroma. T cell proximity to tumor cells was evaluated as difference in area under the curve between i) a spatial G-function quantifying T cell density around tumor cells in tumor areas and ii) analogous null distributions obtained by random permutation of cell labels. This assessment of co-clustering is independent of cell density and heterogeneity therein and does not reflect repulsion of T cells to stromal/marginal areas. Clinical characteristics, RECIST response and survival were collected from patient records. Associations between T cell density, T cell proximity to Sox10/Melan-A+ tumor cells, other clinical biomarkers (LDH, M stage and WHO performance status) and response were examined in a Bayesian hierarchical logistic regression. Results: Tumor specimens of 98 patients were included, of whom 45 were treated with aPD1 as first-line therapy and 33 had an objective response. CD8 T cell proximity to tumor cells was associated with response in an independent, comparatively strong, and tissue dependent manner (cutaneous tissue: 2.78 [2.45, 3.17], visceral: 2.30 [1.95, 2.72], lymphoid: 2.12 [1.88, 2.40], format: maximal posteriori odds ratio [89% equal-tailed credibility interval]), in a multivariate model correcting for CD8 T cell density (1.74 [1.62, 1.88]), LDH (1.93 [1.72, 2.16]), M stage (0.92 [0.87, 0.98]) and WHO performance status (0.79 [0.72, 0.88]). Our model achieved an area under the ROC curve of 77.7%, whereas an analogous model omitting the proximity variable achieved 73.1%. Conclusions: Our analyses show that spatial proximity of CD8 T cells to tumor cells functions as an independent biomarker for response to aPD1 and suggests that preexisting CD8 T cell tumor reactivity is reflected by this spatial proximity.


2020 ◽  
Author(s):  
Sun Tian ◽  
Fulong Wang ◽  
Rongxin Zhang ◽  
Gong Chen

Abstract MSI/MSS status does not fully explain cancer immunotherapy response in colorectal cancer. We used gene expression data of 454 samples (MSI=131, MSI-L=23, MSS=284, Unknown=16) and developed a method TMEPRE that models colorectal cancer specific signature of CD8+ T cell infiltration and CD8+ T cell exhaustion states. TMEPRE showed predictive power in three datasets of anti-PD1 treated patients(p=0.056, 0.115, 0.003). CD8+ T cell exhaustion component of TMEPRE model correlates with anti-PD1 responding progenitor exhausted CD8+ T cells in both tumor and viral infection(p=0.048, 0.001). Global pattern of TMEPRE on 454 colorectal cancer samples indicated that 10.6% of MSS patients and 67.2% of MSI patients show biological characters that can benefit from anti-PD1 treatment. Within MSI nonresponders, approximately 50% showed no sufficient amount of tumor infiltrating CD8+ T cells and 50% showed terminal exhaustion of CD8+ T cells. These terminally exhausted CD8+ T cells coexisted with signature of myeloid-derived suppressor cells in colorectal cancer.


2020 ◽  
Author(s):  
Peng Yang ◽  
Pan Xiong ◽  
Yuanning Guo ◽  
Haihua Huang ◽  
Shaobin Chen ◽  
...  

Abstract Background: Infiltrating T lymphocytes within tumors have been recognized to be associated with patient survival in various cancer types. For esophageal squamous cell carcinoma (ESCC), the prognostic implications of infiltrating CD3+ and CD8+ T cells have yet to be validated in more extensive patient groups.Methods: We evaluated the numbers of infiltrating CD3+ and CD8+ T cells within tumors from 461 patients with ESCC using immunohistochemistry and analyzed its impacts on overall survival.Results: The median number of infiltrating CD3+ and CD8+ T cell per field was 16.0 (P25-P75: 9.2-28.6) and 8.0 (3.8-20.2), respectively, with obvious correlation between them (rs = 0.65, p < 0.0001). Age and tumor grade were associated with the numbers of infiltrating T cells (all p < 0.05). A high number of infiltrating CD3+ T cells was associated with prolonged overall survival (unadjusted HR for high vs low: 0.73, 95% CI: 0.55-0.98), whereas CD8+ T cell number was not (0.90, 0.68-1.20). Multivariate Cox analysis identified that T stage, lymph node metastasis, and infiltrating CD3+ T cell number were independent prognostic factors (all p < 0.05).Conclusions: Our results indicate that CD3+ T cell infiltration within tumors is an independent prognostic factor for ESCC patients, whereas CD8+ T cell infiltration has no prognostic implications.


2019 ◽  
Vol 5 (3) ◽  
pp. 63
Author(s):  
Alice Bayiyana ◽  
Samuel Okurut ◽  
Rose Nabatanzi ◽  
Godfrey Zziwa ◽  
David R. Boulware ◽  
...  

Despite improvement in the prognosis of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) patients on antiretroviral therapy (ART), cryptococcal meningitis (CM) still causes 10–15% mortality among HIV-infected patients. The immunological impact of ART on the CD4+ and CD8+ T cell repertoire during cryptococcal co-infection is unclear. We determined longitudinal phenotypic changes in T cell subsets among patients with CM after they initiated ART. We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+ and CD8+ T cells during CM co-infection. For this substudy, peripheral blood mononuclear cells (PBMC) were isolated at four time points from CM patients following ART initiation during the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+ and CD8+ T cells was done using T cell surface marker monoclonal antibodies by flow cytometry. There was variation in the expression of immunophenotypic markers defining central memory (CD27+CD45R0+), effector memory (CD45R0+CD27–), immune activation (CD38+ and Human Leucocyte Antigen DR (HLA-DR+), and exhaustion (Programmed cell death protein one (PD-1) in the CD4+ T cell subset. In comparison to the CD4+ T cell population, the CD8+ central memory subset declined gradually with minimal increase in the effector memory subset. Both CD4+ and CD8+ T cell immune exhaustion and activation markers remained elevated over 12 weeks. The relative surge and decline in the expression of T cell surface markers outlines a variation in the differentiation of CD4+ T cells during ART treatment during CM co-infection.


Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1994-1995 ◽  
Author(s):  
Masako Moriuchi ◽  
Hiroyuki Moriuchi

Abstract Although it is widely believed that viral clearance is mediated principally by the destruction of infected cells by cytotoxic T cells, noncytolytic antiviral activity of CD8+ T cells may play a role in preventing the progression to disease in infections with immunodeficiency viruses and hepatitis B virus. We demonstrate here that (1) replication of human T-lymphotropic virus type I (HTLV-I) is more readily detected from CD8+ T-cell–depleted (CD8−) peripheral blood mononuclear cells (PBMCs) of healthy HTLV-I carriers than from unfractionated PBMCs, (2) cocultures of CD8− PBMCs with autologous or allogeneic CD8+ T cells suppressed HTLV-I replication, and (3) CD8+ T-cell anti-HTLV-I activity is not abrogated intrans-well cultures in which CD8+ cells are separated from CD8− PBMCs by a permeable membrane filter. These results suggest that class I-unrestricted noncytolytic anti–HTLV-I activity is mediated, at least in part by a soluble factor(s), and may play a role in the pathogenesis of HTLV-I infection.


Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 956
Author(s):  
Kirsten Freitag ◽  
Sara Hamdan ◽  
Matthias J. Reddehase ◽  
Rafaela Holtappels

CD8+ T-cell responses to pathogens are directed against infected cells that present pathogen-encoded peptides on MHC class-I molecules. Although natural responses are polyclonal, the spectrum of peptides that qualify for epitopes is remarkably small even for pathogens with high coding capacity. Among those few that are successful at all, a hierarchy exists in the magnitude of the response that they elicit in terms of numbers of CD8+ T cells generated. This led to a classification into immunodominant and non-immunodominant or subordinate epitopes, IDEs and non-IDEs, respectively. IDEs are favored in the design of vaccines and are chosen for CD8+ T-cell immunotherapy. Using murine cytomegalovirus as a model, we provide evidence to conclude that epitope hierarchy reflects competition on the level of antigen recognition. Notably, high-avidity cells specific for non-IDEs were found to expand only when IDEs were deleted. This may be a host’s back-up strategy to avoid viral immune escape through antigenic drift caused by IDE mutations. Importantly, our results are relevant for the design of vaccines based on cytomegaloviruses as vectors to generate high-avidity CD8+ T-cell memory specific for unrelated pathogens or tumors. We propose the deletion of vector-encoded IDEs to avoid the suppression of epitopes of the vaccine target.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Min Deng ◽  
Shao-Hua Li ◽  
Xu Fu ◽  
Xiao-Peng Yan ◽  
Jun Chen ◽  
...  

Abstract Background Programmed death- ligand 1 (PD-L1) seems to be associated with the immune escape of tumors, and immunotherapy may be a favorable treatment for PD-L1-positive patients. We evaluated intrahepatic cholangiocarcinoma (ICC) specimens for their expression of PD-L1, infiltration of CD8+ T cells, and the relationship between these factors and patient survival. Methods In total, 69 resections of ICC were stained by immunohistochemistry for PD-L1, programmed death factor-1 (PD-1), and CD8+ T cells. CD8+ T-cell densities were analyzed both within tumors and at the tumor-stromal interface. Patient survival was predicted based on the PD-L1 status and CD8+ T-cell density. Results The expression rate of PD-L1 was 12% in cancer cells and 51% in interstitial cells. The expression rate of PD-1 was 30%, and the number of CD8+ T-cells increased with the increase of PD-L1 expression (p < 0.05). The expression of PD-L1 in the tumor was correlated with poor overall survival(OS) (p = 0.004), and the number of tumor and interstitial CD8+ T-cells was correlated with poor OS and disease-free survival (DFS) (All p < 0.001). Conclusions The expression of PD-L1 in the tumor is related to poor OS, and the number of tumor or interstitial CD8+ T-cells is related to poor OS and DFS. For patients who lose their chance of surgery, PD-L1 immunosuppressive therapy may be the focus of future research as a potential treatment.


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