Development of a Metastasis-Related Immune Prognostic Model of Metastatic Colorectal Cancer and Its Usefulness to Immunotherapy

Background: Post-surgical recurrence of the metastatic colorectal cancer (mCRC) remains a challenge, even with adjuvant therapy. Moreover, patients show variable outcomes. Here, we set to identify gene models based on the perspectives of intrinsic cell activities and extrinsic immune microenvironment to predict the recurrence of mCRC and guide the adjuvant therapy.Methods: An RNA-based gene expression analysis of CRC samples (total = 998, including mCRCs = 344, non-mCRCs = 654) was performed. A metastasis-evaluation model (MEM) for mCRCs was developed using the Cox survival model based on the prognostic differentially expressed genes between mCRCs and non-mCRCs. This model separated the mCRC samples into high- and low-recurrence risk clusters that were tested using machine learning to predict recurrence. Further, an immune prognostic model (IPM) was built using the COX survival model with the prognostic differentially expressed immune-related genes between the two MEM risk clusters. The ability of MEM and IPM to predict prognosis was analyzed and validated. Moreover, the IPM was utilized to evaluate its relationship with the immune microenvironment and response to immuno-/chemotherapy. Finally, the dysregulation cause of IPM three genes was analyzed in bioinformatics.Results: A high post-operative recurrence risk was observed owing to the downregulation of the immune response, which was influenced by MEM genes (BAMBI, F13A1, LCN2) and their related IPM genes (SLIT2, CDKN2A, CLU). The MEM and IPM were developed and validated through mCRC samples to differentiate between low- and high-recurrence risk in a real-world cohort. The functional enrichment analysis suggested pathways related to immune response and immune system diseases as the major functional pathways related to the IPM genes. The IPM high-risk group (IPM-high) showed higher fractions of regulatory T cells (Tregs) and smaller fractions of resting memory CD4+ T cells than the IPM-low group. Moreover, the stroma and immune cells in the IPM-high samples were scant. Further, the IPM-high group showed downregulation of MHC class II molecules. Additionally, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and GDSC analysis suggested the IPM-low as a promising responder to anti-CTLA-4 therapy and the common FDA-targeted drugs, while the IPM-high was non-responsive to these treatments. However, treatment using anti-CDKN2A agents, along with the activation of major histocompatibility complex (MHC) class-II response might sensitize this refractory mCRC subgroup. The dysfunction of MEIS1 might be the reason for the dysregulation of IPM genes.Conclusions: The IPM could identify subgroups of mCRC with a distinct risk of recurrence and stratify the patients sensitive to immuno-/chemotherapy. Further, for the first time, our study highlights the importance of MHC class-II molecules in the treatment of mCRCs using immunotherapy.

Download Full-text

Recurrence after surgery for concurrent metastatic colorectal cancer: The perspective of bioinformatics and machine learning.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.4043 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 4043-4043

Author(s):

Zhiwen Luo ◽

Xinyu Bi

Keyword(s):

Machine Learning ◽

Mhc Class Ii ◽

Recurrence Risk ◽

Class Ii ◽

Postoperative Recurrence ◽

Functional Enrichment ◽

Postoperative Treatment ◽

Immune Microenvironment ◽

Gene Models ◽

Mhc Class Ii Molecules

4043 Background: Recurrence of concurrent metastatic colorectal cancers (mCRCs) after surgery is still a challenge. But mCRCs’ outcomes are heterogeneous, and no clinicopathological methods can predict its recurrence and guide postoperative treatment from an intrinsic cell activities and extrinsic immune microenvironment perspective. We aimed to identify such gene models. Methods: Gene expression analysis on CRCs. Based on metastasis-related genes, a metastatic evaluation model (MEM) was developed, dividing mCRCs into high and low recurrence risk clusters. Machine learning tested MEM’s importance to predict recurrence. Further investigating MEM’s two clusters made an immune prognostic model (IPM) with immune genes differentially expressed between MEM clusters. The predictive performance of MEM and IPM on prognosis was comprehensively analyzed and validated. The mechanism of IPM on the immune microenvironment and response to immuno/chemotherapy was analyzed extensively. Results: RNA data of 998 CRCs were analyzed. High postoperative recurrence risk in mCRCs was owing to immune response’s down-regulation, which was influenced by 3 MEM genes ( BAMBI, F13A1, LCN2) and their related 3 IPM genes ( SLIT2, CDKN2A, CLU). MEM and IPM were developed and validated on 239 mCRCs to differentiate a low and high recurrence risk (AUCs > 0.7). Functional enrichment analysis showed immune response and immune system diseases pathway represented the major function and pathway related to IPM gene. IPM high-risk group (IPM-high) had higher fractions of Tregs ( P= 0.04), lower fractions of resisting memory CD4+ T cells ( P= 0.02) than IPM-low. And stroma and immune cells in IPM-high samples were scant ( P= 0.0002, 0.001, respectively). In IPM-high, MHC class II molecules all down-expressed, and DNA methylation disordered. TIDE algorithm and GDSC analysis discovered IPM-low was more promising to respond to both anti-CTLA4 therapy ( P= 0.005) and common FDA targeted drugs ( P< 0.05), while IPM-high had nonresponse to both of them. But anti-CDKN2A agent with activation of MHC class II response might reverse the dilemma of this refractory mCRCs subgroup. Conclusions: Postoperative recurrence of mCRC is strongly related to immune microenvironment. Our two relative gene models could identify subgroups of mCRC with different recurrence risk, and stratify mCRCs sensitive to immune/chemotherapy, even highlight the ignored importance of MHC class II molecules on immunotherapy in mCRCs for the first time.

Download Full-text

MHC Sınıf I ve MHC Sınıf II Gen Düzenlenmesi

Turkish Journal of Immunology ◽

10.25002/tji.2020.1364 ◽

2020 ◽

Vol 8 (3) ◽

pp. 144-156

Author(s):

Şule KARATAŞ ◽

Fatma SAVRAN OĞUZ

Keyword(s):

Immune Response ◽

T Cells ◽

Gene Regulation ◽

Mhc Class I ◽

Mhc Class Ii ◽

Class Ii ◽

Class I ◽

Mhc Molecules ◽

Class Ii Mhc ◽

Regulation Mechanisms

Introduction: Peptides obtained by processing intracellular and extracellular antigens are presented to T cells to stimulate the immune response. This presentation is made by peptide receptors called major histocompatibility complex (MHC) molecules. The regulation mechanisms of MHC molecules, which have similar roles in the immune response, especially at the gene level, have significant differences according to their class. Objective: Class I and class II MHC molecules encoded by MHC genes on the short arm of the sixth chromosome are peptide receptors that stimulate T cell response. These peptides, which will enable the recognition of the antigen from which they originate, are loaded into MHC molecules and presented to T cells. Although the principles of loading and delivering peptides are similar for both molecules, the peptide sources and peptide loading mechanisms are different. In addition, class I molecules are expressed in all nucleated cells while class II molecules are expressed only in Antigen Presentation Cells (APC). These differences; It shows that MHC class I is not expressed by exactly the same transcriptional mechanisms as MHC class II. In our article, we aimed to compare the gene expressions of both classes and reveal their similarities and differences. Discussion and Conclusion: A better understanding of the transcriptional mechanisms of MHC molecules will reveal the role of these molecules in diseases more clearly. In our review, we discussed MHC gene regulation mechanisms with presence of existing informations, which is specific to the MHC class, for contribute to future research. Keywords: MHC class I, MHC class II, MHC gene regulation, promoter, SXY module, transcription

Download Full-text

Synaptic Clusters of MHC Class II Molecules Induced on DCs by Adhesion Molecule–mediated Initial T-Cell Scanning

Molecular Biology of the Cell ◽

10.1091/mbc.e05-01-0005 ◽

2005 ◽

Vol 16 (7) ◽

pp. 3314-3322 ◽

Cited By ~ 54

Author(s):

Hortensia de la Fuente ◽

María Mittelbrunn ◽

Lorena Sánchez-Martín ◽

Miguel Vicente-Manzanares ◽

Amalia Lamana ◽

...

Keyword(s):

T Cells ◽

Mhc Class Ii ◽

Class Ii ◽

Regulatory Pathway ◽

Immune Synapse ◽

Mhc Ii ◽

Cytoskeleton Reorganization ◽

Adhesive Contacts ◽

Enhance Antigen Presentation ◽

Mhc Class Ii Molecules

Initial adhesive contacts between T lymphocytes and dendritic cells (DCs) facilitate recognition of peptide-MHC complexes by the TCR. In this report, we studied the dynamic behavior of adhesion and Ag receptors on DCs during initial contacts with T-cells. Adhesion molecules LFA-1- and ICAM-1,3-GFP as well as MHC class II-GFP molecules were very rapidly concentrated at the DC contact area. Binding of ICAM-3, and ICAM-1 to a lesser extent, to LFA-1 expressed by mature but not immature DC, induced MHC-II clustering into the immune synapse. Also, ICAM-3 binding to DC induced the activation of the Vav1-Rac1 axis, a regulatory pathway involved in actin cytoskeleton reorganization, which was essential for MHC-II clustering on DCs. Our results support a model in which ICAM-mediated MHC-II clustering on DC constitutes a priming mechanism to enhance antigen presentation to T-cells.

Download Full-text

Major histocompatibility complex-restricted recognition of retroviral superantigens by V beta 17+ T cells.

Journal of Experimental Medicine ◽

10.1084/jem.176.1.275 ◽

1992 ◽

Vol 176 (1) ◽

pp. 275-280 ◽

Cited By ~ 15

Author(s):

M A Blackman ◽

F E Lund ◽

S Surman ◽

R B Corley ◽

D L Woodland

Keyword(s):

T Cells ◽

Major Histocompatibility Complex ◽

Mhc Class Ii ◽

Class Ii ◽

Major Histocompatibility ◽

Direct Role ◽

Histocompatibility Complex ◽

Class Ii Mhc ◽

Mhc Class Ii Molecules

It has been established that at least some V beta 17+ T cells interact with an endogenous superantigen encoded by the murine retrovirus, Mtv-9. To analyze the role of major histocompatibility complex (MHC) class II molecules in presenting the Mtv-9 encoded superantigen, vSAG-9 to V beta 17+ hybridomas, a panel of nine hybridomas was tested for their ability to respond to A20/2J (H-2d) and LBK (H-2a) cells which had been transfected with the vSAG-9 gene. Whereas some of the hybridomas recognized vSAG-9 exclusively in the context of H-2a, other hybridomas recognized vSAG-9 exclusively in the context of H-2d or in the context of both H-2d and H-2a. These results suggest that: (a) the class II MHC molecule plays a direct role in the recognition of retroviral superantigen by T cells, rather than serving simply as a platform for presentation; and, (b) it is likely that components of the TCR other than V beta are involved in the vSAG-9/TCR/class II interaction.

Download Full-text

Activation of Human Dendritic Cells Is Modulated by Components of the Outer Membranes of Neisseria meningitidis

Infection and Immunity ◽

10.1128/iai.71.10.5590-5597.2003 ◽

2003 ◽

Vol 71 (10) ◽

pp. 5590-5597 ◽

Cited By ~ 21

Author(s):

Tamara Al-Bader ◽

Myron Christodoulides ◽

John E. Heckels ◽

Judith Holloway ◽

Amanda E. Semper ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Neisseria Meningitidis ◽

Mrna Expression ◽

Mhc Class Ii ◽

Human Monocyte ◽

Class Ii ◽

Effective Vaccine ◽

Tlr4 Mrna ◽

Mhc Class Ii Molecules

ABSTRACT Neisseria meningitidis serogroup B is a major cause of life-threatening meningitis and septicemia worldwide, and no effective vaccine is available. Initiation of innate and acquired immune responses to N. meningitidis is likely to be dependent on cellular responses of dendritic cells (DC) to antigens present in the outer membrane (OM) of the meningococcus. In this study, the responses of human monocyte-derived DC (mo-DC) to OM isolated from parent (lipopolysaccharide [LPS]-replete) meningococci and from a mutant deficient in LPS were investigated. Parent OM selectively up-regulated Toll-like receptor 4 (TLR4) mRNA expression and induced mo-DC maturation, as reflected by increased production of chemokines, proinflammatory cytokines, and CD83, CD80, CD86, CD40, and major histocompatibility complex (MHC) class II molecules. In contrast, LPS-deficient OM selectively up-regulated TLR2 mRNA expression and induced moderate increases in both cytokine production and expression of CD86 and MHC class II molecules. Preexposure to OM, with or without LPS, augmented the allostimulatory properties of mo-DC, which induced proliferation of naive CD4+ CD45RA+ T cells. In addition, LPS-replete OM induced a greater gamma interferon/interleukin-13 ratio in naive T cells, whereas LPS-deficient OM induced the reverse profile. These data demonstrate that components of the OM, other than LPS, are also likely to be involved in determining the levels of DC activation and the nature of the T-helper immune response.

Download Full-text

In Vivo Evidence for the Contribution of Human Histocompatibility Leukocyte Antigen (Hla)-Dq Molecules to the Development of Diabetes

Journal of Experimental Medicine ◽

10.1084/jem.191.1.97 ◽

2000 ◽

Vol 191 (1) ◽

pp. 97-104 ◽

Cited By ~ 74

Author(s):

Li Wen ◽

F. Susan Wong ◽

Jie Tang ◽

Ning-Yuan Chen ◽

Martha Altieri ◽

...

Keyword(s):

T Cells ◽

Transgenic Mice ◽

Mhc Class Ii ◽

Spontaneous Diabetes ◽

Class Ii ◽

Β Cells ◽

Leukocyte Antigen ◽

Hla Dqa1 ◽

Mhc Class Ii Molecules

Although DQA1*0301/DQB1*0302 is the human histocompatibility leukocyte antigen (HLA) class II gene most commonly associated with human type 1 diabetes, direct in vivo experimental evidence for its diabetogenic role is lacking. Therefore, we generated C57BL/6 transgenic mice that bear this molecule and do not express mouse major histocompatibility complex (MHC) class II molecules (DQ8+/mII−). They did not develop insulitis or spontaneous diabetes. However, when DQ8+/mII− mice were bred with C57BL/6 mice expressing costimulatory molecule B7-1 on β cells (which normally do not develop diabetes), 81% of the DQ8+/mII−/B7-1+ mice developed spontaneous diabetes. The diabetes was accompanied by severe insulitis composed of both T cells (CD4+ and CD8+) and B cells. T cells from the diabetic mice secreted large amounts of interferon γ, but not interleukin 4, in response to DQ8+ islets and the putative islet autoantigens, insulin and glutamic acid decarboxylase (GAD). Diabetes could also be adoptively transferred to irradiated nondiabetic DQ8+/mII−/B7-1+ mice. In striking contrast, none of the transgenic mice in which the diabetes protective allele (DQA1*0103/DQB1*0601, DQ6 for short) was substituted for mouse MHC class II molecules but remained for the expression of B7-1 on pancreatic β cells (DQ6+/mII−/B7-1+) developed diabetes. Only 7% of DQ−/mII−/B7-1+ mice developed diabetes at an older age, and none of the DQ−/mII+/B7-1+ mice or DQ8+/mII+/B7-1+ mice developed diabetes. In conclusion, substitution of HLA-DQA1*0301/DQB1*0302, but not HLA-DQA1*0103/DQB1*0601, for murine MHC class II provokes autoimmune diabetes in non–diabetes-prone rat insulin promoter (RIP).B7-1 C57BL/6 mice. Our data provide direct in vivo evidence for the diabetogenic effect of this human MHC class II molecule and a unique “humanized” animal model of spontaneous diabetes.

Download Full-text

The importance of the back–signal from T cells into antigen–presenting cells in determining susceptibility to parasites

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1997.0117 ◽

1997 ◽

Vol 352 (1359) ◽

pp. 1327-1330 ◽

Cited By ~ 7

Author(s):

Brigitte Müller ◽

Avrion Mitchison

Keyword(s):

T Cells ◽

Immune Responses ◽

Mhc Class Ii ◽

Class Ii ◽

Activated T Cells ◽

Ifn Gamma ◽

Parasite Infections ◽

Antigen Presenting ◽

Mhc Class Ii Genes ◽

Mhc Class Ii Molecules

It has long been known that certain MHC class II genes can dominantly suppress immune responses and so increase susceptibility to parasite infections, but the mechanism has been unclear. Recent work has revealed one way in which this form of suppression may operate through gating by MHC class II molecules of the back–signal from activated T cells into macrophages. The two known suppressive genes of the mouse are expressed in macrophages more extensively than are other class II genes. This is asscociated with suppresion of IL–4 production resulting, we infer, from overproduction in the macrophages of IL–12, the counter–cytokine to IL–4. The lack of IL–4 may itself be immunosuppressive, even for Th2 responses, and excess IL–12 can overinduce the antiproliferative cytokine IFN–gamma. Although this mechanism requires further substantiation, we believe that it offers a reasonable answer to an old conundrum.

Download Full-text

Major Histocompatibility Complex Class II-Independent Generation of Neutralizing Antibodies against T-Cell-Dependent Borrelia burgdorferi Antigens Presented by Dendritic Cells: Regulation by NK and γδ T Cells

Infection and Immunity ◽

10.1128/iai.69.4.2407-2415.2001 ◽

2001 ◽

Vol 69 (4) ◽

pp. 2407-2415 ◽

Cited By ~ 11

Author(s):

M. Lamine Mbow ◽

Nordin Zeidner ◽

Robert D. Gilmore ◽

Marc Dolan ◽

Joseph Piesman ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Major Histocompatibility Complex ◽

Borrelia Burgdorferi ◽

Mhc Class Ii ◽

Γδ T Cells ◽

Humoral Response ◽

Class Ii ◽

Histocompatibility Complex ◽

Mhc Class Ii Molecules

ABSTRACT We previously showed that adoptive transfer of Borrelia burgdorferi-pulsed dendritic cells (DCs) into syngeneic mice protects animals from challenge with tick-transmitted spirochetes. Here, we demonstrate that the protective immune response is antibody (Ab) dependent and does not require the presence of major histocompatibility complex (MHC) class II molecules on DCs. Mice sensitized with B. burgdorferi-pulsed MHC class II-deficient (MHC class II−/−) DCs mounted a humoral response against protective antigens, includingB. burgdorferi outer surface protein A (OspA) and OspC. B-cell help for the generation of neutralizing anti-OspC immunoglobulin G Abs could be provided by γδ T cells. In contrast, anti-OspA Ab production required the presence of αβ T cells, although this pathway could be independent of MHC class II molecules on antigen-presenting cells. Moreover, depletion of NK cells prior to transfer of antigen-pulsed MHC class II−/− DCs resulted in significant increases in the levels of neutralizing Abs induced by DCs. Altogether, these data suggest that the initial interactions between DCs and innate immune cells, such as γδ and NK cells, can influence the generation of a protective humoral response againstB. burgdorferi antigens.

Download Full-text