scholarly journals Correlation between schistosomiasis and CD8+ T cell and stromal PD-L1 as well as the different prognostic role of CD8+ T cell and PD-L1 in schistosomal-associated colorectal cancer and non-schistosomal-associated colorectal cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Weixia Wang ◽  
Hongyan Jing ◽  
Jican Liu ◽  
Dacheng Bu ◽  
Yingyi Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Independent Predictor ◽  
Immunohistochemical Analysis ◽  
Cd8 T Cell ◽  
Prognosis Factor ◽  
Independent Predictive Factor

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.

scholarly journals CD8+ T Cell Densities and Stromal PD-L1 but not Tumoral PD-L1 Associated with Favorable Prognosis in Schistosomal Colorectal Cancer

2021 ◽  
Author(s):  
Weixia Wang ◽  
Hongyan Jing ◽  
Jican Liu ◽  
Dacheng Bu ◽  
Yingyi Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Independent Predictor ◽  
Immunohistochemical Analysis ◽  
Prognosis Factor ◽  
Independent Predictive Factor ◽  
Favorable Prognosis ◽  
Total Cohort ◽  
Cell Densities ◽  
And Gender

Abstract Backgroud: It was known that the expression of programmed cell death-ligand 1 (PD-L1) was correlated with CD8+ T cells, which could produce IFNγ. The effect of infection of Schistosoma japonicum on CD8+ T cells and then on PD-L1 expression was unknown and the utility of CD8+ TILs as a biomarker for schistosomal CRC (SCRC) has rarely been reported. Methods: A total of 338 patients with CRC were enrolled. Immunohistochemical analysis was conducted to evaluate the expression of PD-L1, infiltration by CD8+ T cells. Results: In the total cohort, results showed that CD8+ TIL density was positively correlated with tumoral and stromal PD-L1 expression (p＜0.05). But there were no correlation between schistosomiasis and CD8+ TILs and PD-L1. Furthermore, CD8+ TIL density, schistosomiasis, TNM stage, lymph nodes positive for CRC and gender were independent predictive factors for overall survival (OS) (p＜0.05). Stromal PD-L1(sPD-L1) but not tumoral PD-L1(tPD-L1) expression was correlated with OS but it was not an independent predictor (p=0.046). In patients without schistosomiasis, CD8+T cells and sPD-L1 were associated with better OS (p＜0.05). In patients with schistosomiasis, CD8+T cells were independent prognosis factor (p=0.05). 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.

scholarly journals CD8+ T cell densities and PD-L1 associated with favorable prognosis in schistosomiasis-associated Colorectal Cancer

2021 ◽  
Author(s):  
Weixia Wang ◽  
Hongyan Jing ◽  
Jican Liu ◽  
Yingyi Zhang ◽  
Ting Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Cd8 T Cells ◽  
Independent Predictor ◽  
Immunohistochemical Analysis ◽  
Predictive Biomarker ◽  
Independent Predictive Factor ◽  
Cell Densities ◽  
And Gender ◽  
Infiltrating Lymphocytes

Abstract Backgroud: The expression of programmed cell death-ligand 1 (PD-L1) was correlated with CD8+ T cells, which could producing IFNγ. The effect of infection of Schistosoma japonicum on CD8+ tumour-infiltrating lymphocytes (TILs) and then on PD-L1 expression has rarely been reported and the utility of CD8+ TILs as a biomarker for colorectal cancer (CRC), especially for schistosomal CRC, are still controversial and needing to be determined in CRC. Methods: A total of 338 patients with CRC were enrolled in this study. Immunohistochemical analysis were performed to evaluated the expression of PD-L1 within tumor cells (tPD-L1) and within stromal cells (sPD-L1), infiltration by CD8+ T cells. Results: In the whole cohort, results showed that CD8+ TIL density was positively correlated with tumoral and stromal PD-L1 expression （p＜0.05）. But there were no correlation between schistosomiasis and PD-L1 and CD8+ TILs. Furthermore, CD8+ TIL density, schistosomiasis, TNM stage, lymph nodes positive for CRC and gender were significantly independent predictive factors for overall survival (OS)（p＜0.05）. Stromal PD-L1 but not tPD-L1 expression was correlated with OS but was not an independent predictor (p=0.046). In patients without schistosomiasis, sPD-L1 was significantly associated with better OS but was not an independent predictor（p =0.004）.However, there were no association between schistosomiasis and OS in patients with schistosomal ifection. Conclusions: Our analysis indicated that CD8+ was an independent predictive factor for OS. And the expression of PD-L1 was positively associated with CD8+ TILs density. There were no correlation between schistosomiasis and PD-L1 and CD8+ TILs. Stromal PD-L1 but not tPD-L1 was significantly associated with OS, but was not an independent prognostic factor. It is proposed that PD-L1 expression in combination with CD8+ TIL could be a useful predictive biomarker in CRC patients.

scholarly journals Role of PD-1 during effector CD8 T cell differentiation

2018 ◽  
Vol 115 (18) ◽  
pp. 4749-4754 ◽  
Author(s):  
Eunseon Ahn ◽  
Koichi Araki ◽  
Masao Hashimoto ◽  
Weiyan Li ◽  
James L. Riley ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Lcmv Infection

PD-1 (programmed cell death-1) is the central inhibitory receptor regulating CD8 T cell exhaustion during chronic viral infection and cancer. Interestingly, PD-1 is also expressed transiently by activated CD8 T cells during acute viral infection, but the role of PD-1 in modulating T cell effector differentiation and function is not well defined. To address this question, we examined the expression kinetics and role of PD-1 during acute lymphocytic choriomeningitis virus (LCMV) infection of mice. PD-1 was rapidly up-regulated in vivo upon activation of naive virus-specific CD8 T cells within 24 h after LCMV infection and in less than 4 h after peptide injection, well before any cell division had occurred. This rapid PD-1 expression by CD8 T cells was driven predominantly by antigen receptor signaling since infection with a LCMV strain with a mutation in the CD8 T cell epitope did not result in the increase of PD-1 on antigen-specific CD8 T cells. Blockade of the PD-1 pathway using anti–PD-L1 or anti–PD-1 antibodies during the early phase of acute LCMV infection increased mTOR signaling and granzyme B expression in virus-specific CD8 T cells and resulted in faster clearance of the infection. These results show that PD-1 plays an inhibitory role during the naive-to-effector CD8 T cell transition and that the PD-1 pathway can also be modulated at this stage of T cell differentiation. These findings have implications for developing therapeutic vaccination strategies in combination with PD-1 blockade.

Tissue Parenchymal Cell Expression of B7-H1 Inhibits Infiltrating T Cell Expansion and Prevents Persistence of Graft-Versus-Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2974-2974
Author(s):  
Xiaofan Li ◽  
Wei He ◽  
Ruishu Deng ◽  
Can Liu ◽  
Miao Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Expansion ◽  
Cd8 T Cell ◽  
Target Tissue ◽  
T Cell Expansion ◽  
Parenchymal Cells

Abstract Abstract 2974 Alloreactive donor CD8+ T cells facilitate engraftment and mediate graft versus leukemia (GVL) effects but also cause graft versus host disease (GVHD) in murine and human recipients after allogeneic hematopoietic cell transplantation (HCT). B7-H1 (PD-L1) expression by antigen-presenting cells has an important role in tolerizing activated T cells by binding to PD-1. We and others previously reported that disruption of binding between B7-H1 and PD-1 augments acute GVHD. Parenchymal cells do not usually express B7-H1 but can be induced by inflammatory cytokines (i.e. IFN-g) to express B7-H1. The role of B7-H1 expression by parenchymal tissue cells in regulating the expansion and persistence of donor CD8+ cells in tissues of mice with GVHD has not yet been evaluated. In the current studies, we evaluated the role of B7-H1 expression by GVHD target tissues in regulating donor CD8+ T cell function in 3 different experimental GVHD systems, using in vivo bioluminescent imaging (BLI), in vivo BrdU-labeling, and in vitro proliferation assays. The first system evaluated the role of B7-H1 expression in TBI-conditioned recipients. In these recipients, injected donor CD8+ T cells showed two waves of expansion that correlated with two phases of clinical GVHD. The first wave of donor CD8+ T cell expansion was associated with upregulated expression of B7-H1 in GVHD target tissues and only weak clinical GVHD. The second wave of donor CD8+ T cell expansion was associated with loss of B7-H1 expression, vigorous donor CD8+ T proliferation and expansion in the GVHD target tissues, and lethal GVHD. In a gain-of-function experiment, B7-H1 expression was induced in hepatocytes by hydrodynamic injection of B7-H1 cDNA during the second wave of T cell expansion in mice with GVHD; this subsequently decreased T cell expansion in the liver and ameliorated GVHD. The second system evaluated the role of B7-H1 expression in anti-CD3-conditioned recipients. In wild-type recipients, injected donor CD8+ T cells had only a single wave of expansion, and the mice had no signs of GVHD. B7-H1 expression by tissue cells (i.e. hepatocytes) was up-regulated, and the tissue infiltrating donor CD8+ T cells were anergic. In B7-H1−/− recipients, injected donor CD8+ T cells proliferated vigorously in GVHD target tissues and caused lethal GVHD.The third system evaluated the role of B7-H1 in unconditioned Rag-2−/− recipients after administration of blocking anti-B7-H1 and in the B7-H1−/−Rag-2−/− chimeras with B7-H1 sufficient Rag-2−/− bone marrow cells, in which B7-H1 deficiency was only in tissue parenchymal cells. Both blockade of B7-H1 and B7-H1 deficiency in parenchymal cells resulted in vigorous donor CD8+ T proliferation in GVHD target tissues and caused lethal GVHD. Taken together, these results show that expression of B7-H1 in GVHD target tissue parenchymal cells plays an important role in regulating the proliferation of infiltrating donor CD8+ T cells and preventing the persistence of GVHD. Our studies also indicate that TBI but not anti-CD3 conditioning can lead to loss of GVHD target tissue cell expression of B7-H1 and persistence of GVHD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Organ- and Disease-Stage-Specific Regulation of Toxoplasma gondii-Specific CD8-T-Cell Responses by CD4 T Cells

2006 ◽  
Vol 74 (10) ◽  
pp. 5790-5801 ◽  
Author(s):  
Sonja Lütjen ◽  
Sabine Soltek ◽  
Simona Virna ◽  
Martina Deckert ◽  
Dirk Schlüter
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Cd8 T Cells ◽  
Functional Activity ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Ifn Γ

ABSTRACT Toxoplasma gondii induces a persistent central nervous system infection, which may be lethally reactivated in AIDS patients with low CD4 T-cell numbers. To analyze the role of CD4 T cells for the regulation of parasite-specific CD8 T cells, mice were infected with transgenic T. gondii expressing the CD8 T-cell antigen β-galactosidase (β-Gal). Depletion of CD4 T cells prior to infection did not affect frequencies of β-Gal876-884-specific (consisting of residues 876 to 884 of β-Gal) CD8 T cells but resulted in a pronounced reduction of intracerebral β-Gal-specific gamma interferon (IFN-γ)-producing and cytolytic CD8 T cells. After cessation of anti-CD4 treatment a normal T. gondii-specific CD4 T-cell response developed, but IFN-γ production of intracerebral β-Gal-specific CD8 T cells remained impaired. The important supportive role of CD4 T cells for the optimal functional activity of intracerebral CD8 T cells was also observed in mice that had been depleted of CD4 T cells during chronic toxoplasmosis. Reinfection of chronically infected mice that had been depleted of CD4 T cells during either the acute or chronic stage of infection resulted in an enhanced proliferation of β-Gal-specific IFN-γ-producing splenic CD8 T cells. However, reinfection of chronically infected mice that had been depleted of CD4 T cells in the acute stage of infection did not reverse the impaired IFN-γ production of intracerebral CD8 T cells. Collectively, these findings illustrate that CD4 T cells are not required for the induction and maintenance of parasite-specific CD8 T cells but, depending on the stage of infection, the infected organ and parasite challenge infection regulate the functional activity of intracerebral CD8 T cells.

Transient NKG2D Blockade Attenuates Graft-Versus-Host Disease While Preserving Graft-Versus-Leukemia Effects

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3242-3242 ◽  
Author(s):  
Mobin Karimi ◽  
Theresa M Leichner ◽  
Atsushi Satake ◽  
David Raulet ◽  
Taku Kambayashi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Allogeneic Hsct ◽  
Isotype Control ◽  
Isotype Control Antibody

Abstract In allogeneic hematopoietic stem cell transplantation (HSCT), identification of mechanisms to control GVHD yet maintain GVL responses is of critical importance. One key effector cell that mediates both GVHD and GVL is the CD8+ T cell, which expands in response to T cell receptor (TCR) stimulation by allogeneic MHC class I molecules during allogeneic HSCT. In addition, co-stimulatory molecules facilitate the TCR-mediated activation process and the effector function of CD8+ T cells. Recent data suggest that NKG2D may play a co-stimulatory role in activation and in augmenting anti-tumor cytotoxic responses of CD8+ T cells. NKG2D is an NK cell-associated receptor that is also expressed on all human CD8+ T cells and on activated/memory mouse CD8+ T cells. NKG2D recognizes a diverse array of MHC-related ligands that are expressed by many tumors and induced on cells under stress such as myeloablative conditioning during HSCT. As the role of NKG2D in allogeneic HSCT is unknown, we hereby investigated the role of NKG2D on CD8+ T cells in a mouse model of GVHD and GVL. Our results show that a large fraction (40-50%) of mouse CD8+ T cells inducibly express NKG2D upon activation by allogeneic MHC in vitro and in vivo. To test the role of NKG2D in GVHD pathogenesis, we employed a major MHC-mismatched mouse model of GVHD involving the transplantation of C57BL/6-derived CD8+ T cells and bone marrow (BM) into lethally irradiated Balb/c mice (B6→Balb/c). Using 3 different approaches to block NKG2D on CD8+ T cells (shRNA-mediated silencing, germline NKG2D deficiency, and antibody blockade), we found that weight loss, clinical score, and survival were significantly improved in transplanted mice with NKG2D blockade. The attenuation in GVHD correlated with a significant reduction in TNFα and IFNγ production, cytotoxicity, and proliferation (BrdU incorporation) by CD8+ T cells. Although CD4+ T cells did not express NKG2D, a protective effect of NKG2D blockade was still observed in GVHD induced by a mixture of CD8+ and CD4+ T cells, albeit to a lesser extent. We next tested the effects of NKG2D on CD8+ T cell-mediated GVL. To this end, irradiated Balb/c mice were transplanted with C57BL/6-derived CD8+ T cells and BM, challenged intravenously with luciferase-positive A20 leukemia cells, and followed by total body imaging of luciferase-expressing cells. Given that NKG2D ligands are constitutively expressed on many tumor cells and plays an important role in their eradication, we predicted that continuous NKG2D blockade would inhibit GVL effects. However, as NKGD ligands are upregulated only transiently on stressed normal tissue, we reasoned that transient NKG2D blockade might be sufficient to attenuate GVHD and allow CD8+ T cells to regain their GVL function. To test this hypothesis, we compared the effect of anti-NKG2D antibody as continuous treatment or as 5-day transient treatment to mice receiving isotype control antibody. As expected, mice that received isotype control antibody cleared the A20 cells but developed severe GVHD. Continuous anti-NKG2D antibody-mediated blockade improved GVHD but also blunted the GVL response leading to increased A20 growth. In contrast, a large proportion of mice transiently treated with anti-NKG2D antibody cleared the A20 cells, while maintaining the attenuated GVHD state. Together, these data support a positive role of NKG2D on CD8+ T cells in mediating GVHD and GVL. Given the transient nature of NKG2D ligand upregulation on stressed tissues, a window of opportunity may exist where transient NKG2D blockade could provide a novel therapeutic strategy for treatment of acute GVHD while preserving the GVL function of CD8+ T cells after allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The lncRNA Snhg1-Vps13D vesicle trafficking system promotes memory CD8 T cell establishment via regulating the dual effects of IL-7 signaling

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yanyan Zhang ◽  
Baohua Li ◽  
Qiang Bai ◽  
Pengcheng Wang ◽  
Gang Wei ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Expression Pattern ◽  
Cd8 T Cells ◽  
Vesicle Trafficking ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Memory Cd8 T Cells ◽  
Memory Cd8 T Cell

AbstractThe efficient induction and long-term persistence of pathogen-specific memory CD8 T cells are pivotal to rapidly curb the reinfection. Recent studies indicated that long-noncoding RNAs expression is highly cell- and stage-specific during T cell development and differentiation, suggesting their potential roles in T cell programs. However, the key lncRNAs playing crucial roles in memory CD8 T cell establishment remain to be clarified. Through CD8 T cell subsets profiling of lncRNAs, this study found a key lncRNA-Snhg1 with the conserved naivehi-effectorlo-memoryhi expression pattern in CD8 T cells of both mice and human, that can promote memory formation while impeding effector CD8 in acute viral infection. Further, Snhg1 was found interacting with the conserved vesicle trafficking protein Vps13D to promote IL-7Rα membrane location specifically. With the deep mechanism probing, the results show Snhg1-Vps13D regulated IL-7 signaling with its dual effects in memory CD8 generation, which not just because of the sustaining role of STAT5-BCL-2 axis for memory survival, but more through the STAT3-TCF1-Blimp1 axis for transcriptional launch program of memory differentiation. Moreover, we performed further study with finding a similar high-low-high expression pattern of human SNHG1/VPS13D/IL7R/TCF7 in CD8 T cell subsets from PBMC samples of the convalescent COVID-19 patients. The central role of Snhg1-Vps13D-IL-7R-TCF1 axis in memory CD8 establishment makes it a potential target for improving the vaccination effects to control the ongoing pandemic.

scholarly journals Targeting Pim2 for Improving T-Cell Effector Function and Promoting Cancer Immunotherapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1720-1720
Author(s):  
Yongxia Wu ◽  
Linlu Tian ◽  
Corey Mealer ◽  
Hee-Jin Choi ◽  
Xue-Zhong Yu
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Effector Function ◽  
Cell Responses ◽  
Deficient Mice

Abstract The Provirus Integration sites for Moloney murine leukemia virus (Pim) kinases are a highly conserved family of serine/threonine kinases. The Pim kinase family is composed of three different isoforms, Pim1, Pim2, and Pim3, which have been studied extensively in tumorigenesis and as a potential therapeutic target in various cancers. We previously reported an unexpected role of Pim2 in negatively regulates T-cell responses to alloantigen and tumor (JCI, 2015, PMID: 29781812). However, the mechanisms by which Pim2 modulates T-cell responses remain largely undefined. In the current study, using genetic Pim2-deficient mouse, we demonstrated a key role of Pim2 in regulating T-cell hemostatic and anti-tumor responses in aging, hematopoietic cell transplantation (HCT), and antigen-specific adoptive T-cell therapy (ACT). We observed that Pim2 was critical for T cells to retain quiescent in aged mice, as thymic Treg development was impaired while effector T-cell differentiation in lymphoid organs, including Tc1/Th1, Tc17/Th17 and follicular helper T cells, was increased in Pim2-deficient mice, but not in Pim1/Pim3-deficient mice. Furthermore, Pim2-deficient mice were capable to completely eradicate syngeneic breast cancer (NT2.5) growth (Figure A). During antigen specific anti-tumor response, adoptively transferred Pim2 -/- CD8 T cells showed enhanced ability for controlling established NT2.5 breast cancer and B16 melanoma (Figure B, C). Mechanistically, loss of Pim2 promoted G1 to S phase cell-cycle progression while reduced apoptosis in CD8 T cells. Pim2 -/- CD8 T cells exhibited elevated effector cytokine production while maintained higher levels of CD62L expression, leading to superior effector function, persistence and anti-tumor activity. Reduced differentiation of exhausted and suppressive subsets were observed in Pim2 -/- CD8 T cells after being adoptively transferred in tumor-bearing mice. In addition, Pim2 deficiency was associated with a higher metabolic potential, reflected by increased glycolysis and oxidative phosphorylation, which was at least partially attributed to a decreased level of autophagy in Pim2 -/- CD8 T cells. To further evaluate the clinical translation potential, we applied a Pim2-specific inhibitor (JP11646) and found that blocking Pim2 improved graft-versus-leukemia activity after autologous HCT and also enhanced CD8 T-cell mediated anti-melanoma effects after ACT in mice (Figure B, C). Furthermore, blocking Pim2 using JP11646 promoted human CD8 T-cell response during polyclonal stimulation and enhanced expansion, effector function and tumor killing ability of human melanoma antigen-specific CD8 T cells (data not shown) and CD19 CAR-T cells (Figure D). Our work demonstrated that Pim2 is a potent and distinct regulator of differentiation and maintenance of T effector cells through modulating metabolism and autophagy. Specifically target Pim2 can serve as a novel strategy for improving cancer immunotherapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prognostic significance of SDF-1 in colorectal cancer depends on CD8+ T-cell density

2020 ◽  
Author(s):  
Alexandros Lalos ◽  
Ali Tülek ◽  
Nadia Tosti ◽  
Robert Mechera ◽  
Alexander Wilhelm ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Cell Density ◽  
Cd8 T Cells ◽  
Prognostic Significance ◽  
Cd8 T Cell ◽  
High Expression ◽  
Prognostic Impact

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.

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