Strong spontaneous tumor neoantigen responses induced by a natural human carcinogen

Abstract

A key to improving cancer immunotherapy will be the identification of tumor-specific “neoantigens” that arise from mutations and augment the resultant host immune response. In this study we identified single nucleotide variants (SNVs) by RNA sequencing of asbestos-induced murine mesothelioma cell lines AB1 and AB1-HA. Using the NetMHCpan 2.8 algorithm, the theoretical binding affinity of predicted peptides arising from high-confidence, exonic, non-synonymous SNVs was determined for the BALB/c strain. The immunoreactivity to 20 candidate mutation-carrying peptides of increased affinity and the corresponding wild-type peptides was determined using interferon-γ ELISPOT assays and lymphoid organs of non-manipulated tumor-bearing mice. A strong endogenous immune response was demonstrated to one of the candidate neoantigens, Uqcrc2; this response was detected in the draining lymph node and spleen. Antigen reactive cells were not detected in non-tumor bearing mice. The magnitude of the response to the Uqcrc2 neoantigen was similar to that of the strong influenza hemagglutinin antigen, a model tumor neoantigen. This work confirms that the approach of RNAseq plus peptide prediction and ELISPOT testing is sufficient to identify natural tumor neoantigens.

Transient Treg depletion enhances therapeutic anti‐cancer vaccination

“…These data are consistent with other pre-clinical studies in which selective depletion of Treg in DEREG mice improved the efficacy of therapeutic vaccination against B16 melanoma [27,28]. Given the recent advances in the identification of tumor neo-antigens [32][33][34][35][36], and progress toward the development of patient-specific cancer vaccines [37,38,41], our findings indicate that targeted modulation of Treg would synergise favorably with other cancer immunotherapies.…”

“…Given the recent advances in the use of immune based cancer therapies, particularly for solid cancers [30,31], the role of Treg suppression in limiting anti-tumor immunity is of great interest. Technological innovations in next generation sequencing (NGS) have enabled the identification of tumorspecific mutated antigens (i.e., neo-antigens) that are uniquely recognized by the host's immune system [32][33][34][35][36]. The ability to identify immunogenic tumor neo-antigens brings cancer immunotherapy to a position where, the development of a patient-specific anti-cancer vaccine is now a reality [35,37,38].…”

The role and therapeutic implications of T cells in cancer of the lung

“…6 In NSCLC, T-cell responses have been noted against lung cancer tumor-associated antigens (TAAs), such as cancertestis antigens (e.g. 7 However, despite T-cell recognition, tumors still develop due to direct tumor immunoediting, immune cell suppression and/or an inhibitory cytokine milieu. 2 In addition, tumor neoantigens, which are antigens expressed exclusively on tumor cells, have also been shown to initiate antitumor immune responses.…”

“…Numerous sources of TAAs and neoantigens arise due to mutation of oncogenes and suppressor genes, re-expression of foetal proteins and oncogenic viral proteins, and/ or overexpression of normal proteins. 2,7 The ability to identify tumor-specific neoantigens via NGS platforms has reinvigorated anticancer vaccination strategies. To identify mutations, patient tumor samples are sequenced using next-generation sequencing (NGS) technology for aberrations compared to their normal cellular DNA.…”

“…2 In addition, tumor neoantigens, which are antigens expressed exclusively on tumor cells, have also been shown to initiate antitumor immune responses. 7 However, despite T-cell recognition, tumors still develop due to direct tumor immunoediting, immune cell suppression and/or an inhibitory cytokine milieu. 8 Immunoediting describes how continual selective pressure exerted on immune-recognised tumor cells can shape a more resistant tumor cell population, leading to outgrowth of tumor cells that can escape immunosurveillance or inhibit immune cell activity.…”