Aurora kinase inhibition sensitizes melanoma cells to T-cell-mediated cytotoxicity.

Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated.

Tumor-targeted silencing of the peptide transporter TAP induces potent antitumor immunity.

Neoantigen burden is a major determinant of tumor immunogenicity, underscored by recent clinical experience with checkpoint blockade therapy. Yet the majority of patients do not express, or express too few, neoantigens, and hence are less responsive to immune therapy. Here we describe an approach whereby a common set of new antigens are induced in tumor cells in situ by transient downregulation of the transporter associated with antigen processing (TAP).

TEIPP antigens for T-cell based immunotherapy of immune-edited HLA class I cancers.

T-cell based immunotherapies through checkpoint blockade or adoptive transfer are effective treatments for a wide range of cancers like melanomas and lung carcinomas that harbor a high mutational load. The HLA class I and class II (HLA-I and HLA-II) presented neoantigens arise from genetic mutations in the cancerous cells and are ideal non-self targets for the T cell-based treatments. Although some cancer patients responded with complete regression, many others are irresponsive to checkpoint blockade treatments, or relapse after initial success.

The Immunogenicity of a Proline-Substituted Altered Peptide Ligand toward the Cancer-Associated TEIPP Neoepitope Trh4 Is Unrelated to Complex Stability.

Human cancers frequently display defects in Ag processing and presentation allowing for immune evasion, and they therefore constitute a significant challenge for T cell-based immunotherapy. We have previously demonstrated that the antigenicity of tumor-associated Ags can be significantly enhanced through unconventional residue modifications as a novel tool for MHC class I (MHC-I)-based immunotherapy approaches. We have also previously identified a novel category of cancer neo-epitopes, that is, T cell epitopes associated with impaired peptide processing (TEIPP), that are selectively presented by MHC-I on cells lacking the peptide transporter TAP.

T Cells Engaging the Conserved MHC Class Ib Molecule Qa-1 with TAP-Independent Peptides Are Semi-Invariant Lymphocytes.

The HLA-E homolog in the mouse (Qa-1) is a conserved MHC class Ib molecule presenting monomorphic peptides to germline-encoded natural killer receptor CD94/NKG2A. Previously, we demonstrated the replacement of this canonical peptide by a diverse peptidome upon deficiency of the TAP peptide transporter. Analysis of this Qa-1-restricted T cell repertoire against these non-mutated neoantigens revealed characteristics of conventional hypervariable CD8 T cells, but also of invariant T cell receptor (TCR)αβ T cells.