Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigens

Abstract

The impact of intratumoral heterogeneity (ITH) and the resultant neoantigen landscape on T cell immunity are poorly understood. ITH is a widely recognized feature of solid tumors and poses distinct challenges related to the development of effective therapeutic strategies, including cancer neoantigen vaccines. Here, we performed deep targeted DNA sequencing of multiple metastases from melanoma patients and observed ubiquitous sharing of clonal and subclonal single nucleotide variants (SNVs) encoding putative HLA class I-restricted neoantigen epitopes. However, spontaneous antitumor CD8+ T cell immunity in peripheral blood and tumors was restricted to a few clonal neoantigens featuring an oligo-/monoclonal T cell-receptor (TCR) repertoire. Moreover, in various tumors of the 4 patients examined, no neoantigen-specific TCR clonotypes were identified despite clonal neoantigen expression. Mature dendritic cell (mDC) vaccination with tumor-encoded amino acid-substituted (AAS) peptides revealed diverse neoantigen-specific CD8+ T responses, each composed of multiple TCR clonotypes. Isolation of T cell clones by limiting dilution from tumor-infiltrating lymphocytes (TILs) permitted functional validation regarding neoantigen specificity. Gene transfer of TCRαβ heterodimers specific for clonal neoantigens confirmed correct TCR clonotype assignments based on high-throughput TCRBV CDR3 sequencing. Our findings implicate immunological ignorance of clonal neoantigens as the basis for ineffective T cell immunity to melanoma and support the concept that therapeutic vaccination, as an adjunct to checkpoint inhibitor treatment, is required to increase the breadth and diversity of neoantigen-specific CD8+ T cells.

Immune Landscape in Tumor Microenvironment: Implications for Biomarker Development and Immunotherapy

“…that enhance the recruitment of immune cells to the inflammation site [ 8 ], including polymorphonuclear neutrophils and eosinophils, monocytes, lymphocytes, natural killer cells (NK), and mature dendritic cells. In this inflammatory context, as well as during the early tumor stage, T lymphocytes recognize the “neoantigens” generated by the high mutational load often associated with cancer cells [ 9 , 10 ]. In particular, naive T cells primed in the lymph nodes migrate to the inflamed TME, wherein antigen recognition can lead to the complete removal of the tumor.…”

Response and survival of metastatic melanoma patients treated with immune checkpoint inhibition for recurrent disease on adjuvant dendritic cell vaccination

“…Recent work by Linette et al strengthens this idea as it implicates immunological ignorance of clonal neoantigens as the basis for ineffective T-cell immunity and suggested to employ DC vaccination as an adjunct to ICI. 36 Our group has previously demonstrated that treatment with ipilimumab following recurrence on DC vaccination might result in improved clinical efficacy of ipilimumab. 37 Furthermore, concurrent administration of DC vaccination and ipilimumab has been tested in two clinical studies, showing the suggestion of synergy with little added toxicity.…”

The Role of Antigen Processing and Presentation in Cancer and the Efficacy of Immune Checkpoint Inhibitor Immunotherapy

“…According to Linette and colleagues, vaccination using DCs appears to be necessary as an adjuvant to ICI therapy since most T cell clones specific for tumor neoantigens have been demonstrated to be naïve and below the limit of detection in patients with melanoma. In other words, a combinational therapy enhances both direct and cross-presentation and has the potential to boost the frequency and diversity of tumor-specific T cells and thus strengthen immune responses [ 176 ]. Finally, numerous studies have explored whether modulation of intratumoral APCs could increase the response to ICI therapies.…”