CIITA-related block of HLA class II expression, upregulation of HLA class I, and heterogeneous expression of immune checkpoints in hepatocarcinomas: implications for new therapeutic approaches

Ramia, Elise; Chiaravalli, Anna Maria; Eddine, Farah Bou Nasser; Tedeschi, Alessandra; Sessa, Fausto; Accolla, Roberto S.; Forlani, Greta

doi:10.1080/2162402x.2018.1548243

Cited by 24 publications

(18 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies have confirmed that some genes can affect HCC due to their occurrence, development, and immune regulation abilities. For example, Elise (Ramia et al, 2019) found that, in HCC cell lines, human leukocyte antigen (HLA) class II expression shortage was caused by the lack of the HLA class II transactivator (i.e., CIITA), and interferon-gamma treatment could not improve the situation. Lee et al (2014) found that CD47(+) HCC cells secreted cathepsin S (CTSS) preferentially using the CTSS/protease-activated receptor 2 (PAR2) loop to regulate liver TICs.…”

Section: Discussionmentioning

confidence: 99%

A Prognostic Model of 15 Immune-Related Gene Pairs Associated With Tumor Mutation Burden for Hepatocellular Carcinoma

Huo

Zang

2020

Front. Mol. Biosci.

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

A Prognostic Model of 15 Immune-Related Gene Pairs Associated With Tumor Mutation Burden for Hepatocellular Carcinoma

Huo

Zang

2020

Front. Mol. Biosci.

View full text Add to dashboard Cite

“…The first important observation was related to the expression of MHC-I and MHC-II in liver cells. While both these molecules were virtually absent in normal liver cells, MHC-I cell surface molecules were expressed at very high level in HCC cells (59). This of course was relevant to purify the MHC-I tumor peptidome and select the appropriate peptides for the vaccine compositions.…”

Section: From the Bench To The Bedside: The Construction Of An Optimamentioning

confidence: 99%

“…Importantly MHC-II expression could not be rescued even by treatment with IFNγ, the most potent inflammatory cytokine that induces MHC-II expression indirectly via the primary transcriptional activation of CIITA (19). In depth analysis of the molecular mechanism responsible of this finding demonstrated that the CIITA promoter IV, the specific promoter activated by the IFNγ (60), was silenced by hypermethylation of its sequence and thus rendered developmentally unresponsive in liver cells (59). This finding may have important effects on the interpretation of the tolerogenic environment of the liver, because the impossibility to express MHC-II molecules by liver cells, continuously in contact with massive concentrations of antigenic materials derived from the digestive tract, would prevent accidental co-participation of these cells to APC function and activation of immune system against potential food antigens as well as other antigens including self antigens.…”

Section: From the Bench To The Bedside: The Construction Of An Optimamentioning

confidence: 99%

CIITA-Driven MHC Class II Expressing Tumor Cells as Antigen Presenting Cell Performers: Toward the Construction of an Optimal Anti-tumor Vaccine

et al. 2019

Self Cite

View full text Add to dashboard Cite

Construction of an optimal vaccine against tumors relies on the availability of appropriate tumor-specific antigens capable to stimulate CD4+ T helper cells (TH) and CD8+ cytolytic T cells (CTL). CTL are considered the major effectors of the anti-tumor adaptive immune response as they recognize antigens presented on MHC class I (MHC-I) molecules usually expressed in all cells and thus also in tumors. However, attempts to translate in clinics vaccination protocols based only on tumor-specific MHC-I-bound peptides have resulted in very limited, if any, success. We believe failure was mostly due to inadequate triggering of the TH arm of adaptive immunity, as TH cells are necessary to trigger and maintain the proliferation of all the immune effector cells required to eliminate tumor cells. In this review, we focus on a novel strategy of anti-tumor vaccination established in our laboratory and based on the persistent expression of MHC class II (MHC-II) molecules in tumor cells. MHC-II are the restricting elements of TH recognition. They are usually not expressed in solid tumors. By genetically modifying tumor cells of distinct histological origin with the MHC-II transactivator CIITA, the physiological controller of MHC-II gene expression discovered in our laboratory, stable expression of all MHC class II genes was obtained. This resulted in tumor rejection or strong retardation of tumor growth in vivo in mice, mediated primarily by tumor-specific TH cells as assessed by both depletion and adoptive cell transfer experiments. Importantly these findings led us to apply this methodology to human settings for the purification of MHC-II-bound tumor specific peptides directly from tumor cells, specifically from hepatocarcinomas, and the construction of a multi-peptide (MHC-II and MHC-I specific) immunotherapeutic vaccine. Additionally, our approach unveiled a noticeable exception to the dogma that dendritic cells are the sole professional antigen presenting cells (APC) capable to prime naïve TH cells, because CIITA-dependent MHC-II expressing tumor cells could also perform this function. Thus, our approach has served not only to select the most appropriate tumor specific peptides to activate the key lymphocytes triggering the anti-tumor effector functions but also to increase our knowledge of intimate mechanisms governing basic immunological processes.

show abstract

“…17 Whereas normal hepatocytes do not express HLA class I and II, HCC cells strongly upregulate HLA class I while remaining negative for HLA class II. 18 The absence of HLA class II expression in HCC cell lines is correlated with a lack of CIITA expression. 18 This supports the hypothesis that MHC-II positive tumor cells could be recognized by the host immune system and help establish a protective immune response.…”

Section: Discussionmentioning

confidence: 99%

“…18 The absence of HLA class II expression in HCC cell lines is correlated with a lack of CIITA expression. 18 This supports the hypothesis that MHC-II positive tumor cells could be recognized by the host immune system and help establish a protective immune response. 19 Briefly, a cross-match involves placing recipient serum (potentially containing donor-specific anti-HLA antibodies) onto donor lymphocytes (containing HLAs).…”

Section: Discussionmentioning

confidence: 99%

Cross-Match as an Immuno-Oncological Risk Factor for Hepatocellular Carcinoma Recurrence and Inferior Survival After Living Donor Liver Transplantation: A Call for Further Investigation

et al. 2020

Clin Med Insights Oncol

View full text Add to dashboard Cite

Background: The success of immunotherapy for patients with hepatocellular carcinoma (HCC) suggests that immune dysregulation occurs in HCC patients. This warrants an immuno-oncological risk assessment in the platform of liver transplantation. Methods: This retrospective single-center study analyzed risk factors for—particularly cross-matching performed through conventional complement-dependent cytotoxicity cross-match tests—and the outcomes of HCC recurrence following living donor liver transplant. Results: A total of 71 patients were included. The median follow-up period was 29.1 months; 17 (23.9%) patients had posttransplant HCC recurrence, and their 1-, 3-, and 5-year-survival rates were 70.6%, 25.7%, and 17.1%, respectively, which were inferior to those of patients without HCC recurrence (87.0%, 80.7%, and 77.2%, respectively; P < .001). In addition to microvascular invasion, positive cross-match results for B cells at 37°C (B- 37°C) or T cells at 4°C (T- 4°C) were associated with inferior overall survival in multivariable analysis after adjustment for tumor status beyond Milan criteria and elevated alpha-fetoprotein levels. Rejection alone cannot be the mechanism underlying the effects of positive cross-match results on patient outcomes. Adjusted survival curves suggested that positive cross-match B- 37°C or T- 4°C was associated with inferior recurrence-free and patient survival, but the robustness of the finding was limited by insufficient power. Conclusions: Additional large-scale studies are required to validate positive cross-match as an immuno-oncological factor associated with HCC recurrence and inferior patient survival.

show abstract

CIITA-related block of HLA class II expression, upregulation of HLA class I, and heterogeneous expression of immune checkpoints in hepatocarcinomas: implications for new therapeutic approaches

Abstract: Forlani (2019) CIITA-related block of HLA class II expression, upregulation of HLA class I, and heterogeneous expression of immune checkpoints in hepatocarcinomas: implications for new therapeutic approaches, OncoImmunology,

Cited by 24 publications

References 60 publications

A Prognostic Model of 15 Immune-Related Gene Pairs Associated With Tumor Mutation Burden for Hepatocellular Carcinoma

A Prognostic Model of 15 Immune-Related Gene Pairs Associated With Tumor Mutation Burden for Hepatocellular Carcinoma

CIITA-Driven MHC Class II Expressing Tumor Cells as Antigen Presenting Cell Performers: Toward the Construction of an Optimal Anti-tumor Vaccine

Cross-Match as an Immuno-Oncological Risk Factor for Hepatocellular Carcinoma Recurrence and Inferior Survival After Living Donor Liver Transplantation: A Call for Further Investigation

Contact Info

Product

Resources

About