banda transcan 2 2016ul

Title: Mutated neo-antigens in hepatocellular carcinoma


Project Coordinator:
Luigi BUONAGURO (Italy) National cancer Institute "Pascale", Department of Experimental Oncology, Napoli


Project Partners:
Danila  VALMORI (France) INSERM U1102 "Cancer Vaccines and Immune Regulation" Institut de Cancerologie de l'Ouest-CLCC René Gauducheau, Saint Herblain
Bruno SANGRO (Spain) Department of Internal Medicine, Hepathology Unit, Universidad de Navarra, Pamplona, Navarra 
Frederic AMANT (Belgium) Oncology Dept. University Hospitals Leuven - KU Leuven
Lucia LOPALCO (Italy) Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele, Milano
Toivo MAIMETS (Estonia) Institute of Molecular and Cell Biology, Competence Centre for Cancer Reaserch, Tallin
Edvins MIKLASEVICS (Latvia) RSU Oncology Institute, Riga


Project Abstract:
Background and rationale: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Immunotherapeutic interventions may help at improving therapeutic outcome in HCC patients. Identification and immunological validation of specific mutated neo-antigens represents an essential knowledge.
Hypothesis: The hypothesis of the present proposal is that identification and immunological validation of mutated neo-antigens specific to HCC will be essential to subsequently develop immunotherapy strategies for improved clinical outcome in HCC patients.
Aims: The primary aim is the identification and immunological validation of mutated neo-antigens specific to HCC. Specific aims will be: 1) evaluate the mutational rate in HCC samples and predict the presentation of neo-epitopes by HLA-A2*01 allele; 2) assess the frequency of specific T cell response to such mutant epitopes in HCC patients, before and after treatment with checkpoint inhibitors (CI); 3) validate the immunogenicity of neo-epitopes in an HLA-transgenic mice and their therapeutic effect in a patient-derived xenograft (PDX) animal model; 4) identify mutated full-length proteins presented on the surface of HCC cancer cells; 5) develop MAbs to such mutated proteins and validate their specificity in vivo in a PDX animal model. Expected results and potential impact: The results of the proposed study will be the identification of HCC-specific target mutated neo-antigens (e.g. epitopes and proteins) and their immuological relevance in a PDX animal model and in HCC patients before and after CI treatment. Such results will have a potential extremely high impact, serving as a foundation for subsequent therapeutic strategies targeting HCC. Mutated neo-antigens will provide a source of immunogens to be used alone or in combination with wild-type antigens identified within the ongoing FP7-funded HEPAVAC project (Coordinator L. Buonaguro). The present HEPAMUT will complement and go far beyond HEPAVAC. 

Final Summary:
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Immunotherapeutic interventions may help at improving therapeutic outcome in HCC patients. Identification and immunological validation of specific mutated neo-antigens represents an essential knowledge. The hypothesis of the present proposal is that identification and immunological validation of mutated neo-antigens specific to HCC will be essential to subsequently develop immunotherapy strategies for improved clinical outcome in HCC patients.

The primary aim is the identification and immunological validation of mutated neo-antigens specific to HCC.

The project has generated valuable results. In particular, an improved algorithm for identification of mutated neo-antigens has been developed, showing also their homology to pathogens’ antigens. Such mutated neoantigens can be targeted by cross-reactive pre-existing T cell immunity, as confirmed in an experimental pre-clinical setting as well as in an HCC long-term survival patient (Petrizzo et al., 2018). The absence of correlation between mutated neoantigens and survival in HCC has been assessed using data available at TCGA (Mauriello et al., Cancers (Basel) (2019) 11:1824). RNA sequencing of 14 paired HCC samples and non-tumoral tissues led to the identification of a median of 1217 missense somatic SNV per patient, narrowed to 30 when filtering by using RNAseq data. A median of 13 and 5 peptides per patient were predicted as potential binders to HLA class I and class II molecules, respectively. Such peptides induced in mice polyfunctional T cells that specifically recognized the mutated but not the wild-type sequence as well as neoantigen-expressing cells. Moreover, co-immunization experiments combining CD8 and CD4 neoantigen epitopes resulted in stronger CD8 T cell responses (Reparaz et al., 2022). Additional, RNA sequencing analysis on 40 paired HCC and non-tumoral tissues sampled at each Partners’ site, with different aetiology, led to identification of a similar median of missense somatic SNV per patient (e.g. 1327). Likewise, a median of 6 peptides per patient were predicted as potential binders to HLA class I. Binding to HLA-class I 02:01 has been experimentally verified. Homology with pathogens’ antigens has been found in approx. 20% of predicted mutated neoantigens. Cross-reactive T cells have been identified in PBMCs from HCC patients (Mauriello et al., submitted for publication). Selected HCC-specific cell-surface membrane proteins have been screened for eliciting targeting monoclonal antibodies (Siracusano et al., 2020; Siracusano et al., submitted for publication).


(Project funded under JTC 2015)


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