The integration of high-throughput technologies and big data analytics is revolutionizing vaccine research. Multi-omics approaches—such as transcriptomics, proteomics, and metabolomics—enable a deeper understanding of immune responses at a cellular and molecular level. AI and machine learning algorithms further enhance vaccine design by predicting antigenic targets and optimizing formulations.
Immuno-oncology has revolutionized the field of cancer therapeutics leading to dramatic improvements in survival in some patients, largely due to the use of immune checkpoint inhibitors (ICIs) for example Keytruda. A detailed analysis of T cell responses in those patients who had a positive therapeutic outcome using immune checkpoint inhibitors ICIs has revealed therapeutically active tumor-reactive T cells that are sufficient to initiate tumor rejection, re-igniting interest in the development of cancer vaccines at a time when global infectious disease challenges have driven advances in vaccination technologies.
Additionally, the discovery of dendritic cells (DCs) act as ‘nature’s adjuvant provided a platform for tumor antigen delivery and has further fueled the expansion of the cancer vaccine field.
Curative anti-tumor T cell immunity has been conceptualized in the framework of the cancer-immunity cycle whereby intra-tumoral dendritic cells (DCs) capture antigens, migrate to draining Lymph nodes, and prime naïve T cells that migrate back to tumors, kill antigen-specific cells, and release more antigens to perpetuate the cycle. As such, dendritic cells (DCs) are critically positioned as vital cells for the activation of a durable, protective T-cell response. Conventional Dendritic cells (DC’s) can be classified into two developmentally distinct subsets: cDC1s efficiently cross-present exogenous antigens on Major Histocompatibility Complex I (MHC I) and secrete Interleukin 12 (IL-12), making them potent stimulators of CD8+ cytotoxic T cells and Th1 T helper cells, while dendric cells, cDC2s may be more important for presentation of Major Histocompatibility Complex II. MHC-II-peptide complexes to CD4+, Th2 and Th17 T helper cells.
cDC1s are required for anti-tumor immunity transporting tumor antigens to draining lymph nodes to prime T cell responses. The importance of this rare population of cells is evidenced by the extensive measures adopted by tumors to exclude cDC1s, with lower levels of cDC1s seen in tumoral tissue compared to healthy tissue. A positive correlation between cDC1 numbers in tumors and patient survival further highlights the critical importance of these cells for anti-cancer immunity.
Unlike cDC1s, which are a relatively homogeneous population of cells, cDC2s are significantly more heterogenous, revealed through single-cell sequencing of patient tumors which demonstrates overlap, at the transcriptional level at least, with non-conventional monocyte-derived dendritic cells. cDC2s prime CD4+ T cell-mediated anti-tumor immunity when released from suppression by tumor regulatory T cells and stimulation with type 1 interferons promotes cDC1-like cross-presentation to CD8+ T cells from cDC2s. These interferon-stimulate gene+ cDC2s may therefore have therapeutic potential, but we still lack understanding of how cDC2 sub-populations are related and their relative contribution to or against anti-tumor immunity; indeed, one study using elegant combinations of genetically modified mice has suggested that, in fact, cDC1 are competent to prime both CD4 and CD8 T cells in tumors.
While the cancer immunity cycle focuses attention on the importance of Dendritic cells to prime naïve tumor-reactive T cells, there is an established body of evidence demonstrating the critical role of intra-tumoral dendritic cells as orchestrators of effector/memory T cell immunity. Production of Interlukein-12 by tumor dendritic cells is required for responsiveness to chemotherapy and immune checkpoint inhibitors and intra-tumoral CCR7neg cDC1s recruit stem cell-like TCF1+ CD8 T cells expressing CXCR3 to form clusters of cells that correlate with improved patient survival. In addition, intra-tumoral CCR7+ DCs, that remain within the tumor microenvironment despite expression of the classic lymph node-homing chemokine receptor CCR7, may be important, although the precise relationship of these cells to other dendritic cell populations is still being studied. CCR7+ dendritic cells cluster around tumor blood vessels and both recruit cytotoxic T cells via production of CXCL16 and ensure their survival due to trans-presentation of Interlukein-15. This previously unappreciated role for dendritic cells within the tumor microenvironment could explain the conundrum of how such a rare population of cells can dominate anti-tumor immunity, concentrating T cell activation and survival within specific intra-tumoral niches; formation of DC-CD4-CD8 ‘triads’ promoted restoration of exhausted T cells and response to Immune checkpoint inhibitors. Targeting dendritic cells to enhance formation of these clusters therefore has exciting therapeutic implications.
With the advent of next-generation sequencing, it has been possible to identify neo-antigens, antigens that arise in tumor cells and are not found in normal tissue, that are specific to each patient, thus allowing the possibility for personalized vaccines. Matched non-malignant and tumor biopsies from a patient are processed for massive parallel sequencing to compare DNA sequences between normal and tumor tissue, and both the normal and tumor samples are aligned to a reference genome. Somatic mutations are called by identifying differences between the reference and the tumor that are not different between the reference and normal tissue. The next step is epitope prediction, the part of the antigen to which an antibody attaches, using various algorithms to predict the binding affinity of predicted antigens to Major Histocompatibility complex (MHC), considering factors such as antigen processing and epitope abundance. Epitope abundance can be classified as present or absent using DNA sequencing or quantified using RNAseq to understand expression levels. Neo-antigen(s) of choice defined as antigens that arise in tumor cells and are not found in healthy tissue are encoded in a vaccine vector and used to immunize the patient. Early proof-of-principle experiments combined the use of exome sequencing and mass spectrometry to predict neo-antigens in the murine tumor lines TrampC1 and MC38. These data demonstrated feasibility of identification of MHC I -binding peptides derived from tumor-specific mutations and generation of therapeutic vaccines in mouse models. This principle was validated in early clinical trials by the Linette lab, who used exome sequencing of resected stage 3 melanomas with in silico modelling to identify potential Human leukocyte Antigen HLA*02-binding mutated peptides. Vaccination with peptide-pulsed autologous, matured dendritic cells resulted in both expansion of neo-antigen-specific T cells, and activation of T cells specific for sub-dominant neo-antigens compared to T cells pre-vaccination, suggesting that vaccination had increased the breadth of the T cell response. These patients had previously received immune checkpoint inhibitors, and overall response data was not collated, so the clinical impact of vaccination is yet to be determined.
Despite decades of unconvincing results, the convergence of our improving understanding of the immune responses that distinguish those patients who respond to immunotherapy, with advances in vaccine technologies, has re-ignited interest in the use therapeutic vaccines to treat cancer patients. Clinical trial data is offering a glimpse of clinical benefit in patients receiving personalized mRNA vaccines with immune checkpoint inhibitors, supporting the notion that cancer vaccines may find their value as immune-modulatory therapies, complementing other interventions rather than priming an anti-tumor T cell response per se. Vaccine developments have been coupled with significant advances in our understanding of tumor dendritic cell biology within the last decade, but this increased knowledge also leads to more questions: which dendritic cell populations orchestrate responses to mRNA vaccines, and do they need to be directly transfected by vaccine antigens; do we need different strategies to target priming or intra-tumoral dendritic cell populations; are all dendritic cell beneficial for tumor regression? It is an exciting time as technical advances allow us to investigate and manipulate anti-tumor immunity with more and more finesse.
Sources:
https://academic.oup.com/immunotherapyadv/article/4/1/ltad030/7486465
