Abstract: Intrinsic genetic instability of tumor cells leads to continuous production of mutated proteins referred to as tumor-specific neoantigens. Generally, they are recognized as nonself products by the host immune system. However, an effective adaptive response clearing neoantigen-expressing cells is lost in tumor diseases. Most advanced therapeutic strategies aim at inducing neoantigen-specific immune activation through personalized approaches. They include tumor cell exome sequencing, human leukocyte antigen (HLA) typing, synthesis, and injection of peptides/RNA with adjuvants. Here, we propose an innovative method to induce a CD8+ T cytotoxic lymphocyte (CTL) immune response against tumor neoantigens bypassing the steps needed in current therapeutic strategies of personalized vaccination. We assumed that tumor cells can be the most efficient and precise factory of major histocompatibility complex (MHC) class I-associated, tumor neoantigen-derived peptides. Hence, endowing tumor cells with professional antigen-presenting functions would prime CD8+ T lymphocytes towards a response against nonself tumor antigens. To explore this possibility, both adenocarcinoma and melanoma human cells were engineered to express both CD80 and CD86 costimulatory molecules. HLA-matched lymphocytes were then primed through cocultivation with the engineered tumor cells. The generation of tumor-specific CD8+ T lymphocytes was tested through the combined analysis of cell activation markers, formation of immunologic synapses, generation of tumor antigen-specific CD8+ T lymphocytes, and cytotoxic activity. Our data consistently indicate that tumor cells endowed with professional antigen-presenting functions can generate an effective tumor-specific CTL immune response. This finding may open avenues towards the development of innovative antitumor immunotherapies. Key messages: We established a novel method to induce antitumor CTLs without a need to identify TAAs and/or tumor neoantigens.This strategy relies on transducing tumor cells with a retroviral vector expressing both CD80 and CD86.In this way, tumor cells prime naïve CD8+ T lymphocytes in a way that CTLs killing the same tumor cells are generated.These findings open the way towards preclinical assays in the perspective to introduce this antitumor immunotherapy strategy in clinic.

Chiozzini, C., Olivetta, E., Sanchez, M., Arenaccio, C., Ferrantelli, F., Leone, P., et al. (2019). Tumor cells endowed with professional antigen-presenting cell functions prime PBLs to generate antitumor CTLs. JOURNAL OF MOLECULAR MEDICINE, 97(8), 1139-1153 [10.1007/s00109-019-01797-7].

Tumor cells endowed with professional antigen-presenting cell functions prime PBLs to generate antitumor CTLs

Arenaccio C.;
2019-01-01

Abstract

Abstract: Intrinsic genetic instability of tumor cells leads to continuous production of mutated proteins referred to as tumor-specific neoantigens. Generally, they are recognized as nonself products by the host immune system. However, an effective adaptive response clearing neoantigen-expressing cells is lost in tumor diseases. Most advanced therapeutic strategies aim at inducing neoantigen-specific immune activation through personalized approaches. They include tumor cell exome sequencing, human leukocyte antigen (HLA) typing, synthesis, and injection of peptides/RNA with adjuvants. Here, we propose an innovative method to induce a CD8+ T cytotoxic lymphocyte (CTL) immune response against tumor neoantigens bypassing the steps needed in current therapeutic strategies of personalized vaccination. We assumed that tumor cells can be the most efficient and precise factory of major histocompatibility complex (MHC) class I-associated, tumor neoantigen-derived peptides. Hence, endowing tumor cells with professional antigen-presenting functions would prime CD8+ T lymphocytes towards a response against nonself tumor antigens. To explore this possibility, both adenocarcinoma and melanoma human cells were engineered to express both CD80 and CD86 costimulatory molecules. HLA-matched lymphocytes were then primed through cocultivation with the engineered tumor cells. The generation of tumor-specific CD8+ T lymphocytes was tested through the combined analysis of cell activation markers, formation of immunologic synapses, generation of tumor antigen-specific CD8+ T lymphocytes, and cytotoxic activity. Our data consistently indicate that tumor cells endowed with professional antigen-presenting functions can generate an effective tumor-specific CTL immune response. This finding may open avenues towards the development of innovative antitumor immunotherapies. Key messages: We established a novel method to induce antitumor CTLs without a need to identify TAAs and/or tumor neoantigens.This strategy relies on transducing tumor cells with a retroviral vector expressing both CD80 and CD86.In this way, tumor cells prime naïve CD8+ T lymphocytes in a way that CTLs killing the same tumor cells are generated.These findings open the way towards preclinical assays in the perspective to introduce this antitumor immunotherapy strategy in clinic.
Chiozzini, C., Olivetta, E., Sanchez, M., Arenaccio, C., Ferrantelli, F., Leone, P., et al. (2019). Tumor cells endowed with professional antigen-presenting cell functions prime PBLs to generate antitumor CTLs. JOURNAL OF MOLECULAR MEDICINE, 97(8), 1139-1153 [10.1007/s00109-019-01797-7].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11590/374101
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