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Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response to ICB of an aggressive low-TMB squamous cell tumor could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous CD4+ and CD8+ T cells. We found that, whereas vaccination with CD4+ or CD8+ NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-L1+ tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic CD4+/CD8+ T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific CD8+ T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. We believe that the concepts explored herein should be exploited for the development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.

CD4 + T cells play key roles in a range of immune responses, either as direct effectors or through accessory cells, including CD8 + T lymphocytes. In cancer, neoantigen (NeoAg)-specific CD8 + T cells capable of direct tumor recognition have been extensively studied, whereas the role of NeoAg-specific CD4 + T cells is less well understood. We have characterized the murine CD4 + T cell response against a validated NeoAg (CLTC H129>Q ) expressed by the MHC-II-deficient squamous cell carcinoma tumor model (SCC VII) at the level of single T cell receptor (TCR) clonotypes and in the setting of adoptive immunotherapy. We find that the natural CLTC H129>Q -specific repertoire is diverse and contains TCRs with distinct avidities as measured by tetramer-binding assays and CD4 dependence. Despite these differences, CD4 + T cells expressing high or moderate avidity TCRs undergo comparable in vivo proliferation to cross-presented antigen from growing tumors and drive similar levels of therapeutic immunity that is dependent on CD8 + T cells and CD40L signaling. Adoptive cellular therapy (ACT) with NeoAg-specific CD4 + T cells is most effective when TCR-engineered cells are differentiated ex vivo with IL-7 and IL-15 rather than IL-2 and this was associated with both increased expansion as well as the acquisition and stable maintenance of a T stem cell memory (T SCM )-like phenotype in tumor-draining lymph nodes (tdLNs). ACT with T SCM -like CD4 + T cells results in lower PD-1 expression by CD8 + T cells in the tumor microenvironment and an increased frequency of PD-1 + CD8 + T cells in tdLNs. These findings illuminate the role of NeoAg-specific CD4 + T cells in mediating antitumor immunity via providing help to CD8 + T cells and highlight their therapeutic potential in ACT. In cancer, neoantigen (NeoAg)-specific CD8 +  T cells capable of direct tumor recognition have been extensively studied but little is known of the role of NeoAg-specific CD4 +  T cells. Here Schoenberger and colleagues analyze an oligoclonal CD4 +  T cell response to a naturally arising murine tumor NeoAg at the level of TCR usage and functionality.

Mutations in cancer cells can result in the production of neoepitopes that can be recognized by T cells and trigger an immune response. A reliable pipeline to identify such immunogenic neoepitopes for a given tumor would be beneficial for the design of cancer immunotherapies. Current methods, such as the pipeline proposed by the Tumor Neoantigen Selection Alliance (TESLA), aim to select short peptides with the highest likelihood to be MHC-I restricted minimal epitopes. Typically, only a small percentage of these predicted epitopes are recognized by T cells when tested experimentally. This is particularly problematic as the limited amount of sample available from patients that are acutely sick restricts the number of peptides that can be tested in practice. This led our group to develop an in-house pipeline termed Identify-Prioritize-Validate (IPV) that identifies long peptides that cover both CD4 and CD8 epitopes. Here, we systematically compared how IPV performs compared to the TESLA pipeline. Patient peripheral blood mononuclear cells were cultured with their corresponding candidate peptides, and immune recognition was measured using cytokine-secretion assays. The IPV pipeline consistently outperformed the TESLA pipeline in predicting neoepitopes that elicited an immune response in our assay. This was primarily due to the inclusion of longer peptides in IPV compared to TESLA. Our work underscores the improved predictive ability of IPV in comparison to TESLA in this assay system and highlights the need to clearly define which experimental metrics are used to evaluate bioinformatic epitope predictions.

Recent years have witnessed a dramatic rise in interest towards cancer epitopes in general and particularly neoepitopes, antigens that are encoded by somatic mutations that arise as a consequence of tumorigenesis. There is also an interest in the specific T cell and B cell receptors recognizing these epitopes, as they have therapeutic applications. They can also aid in basic studies to infer the specificity of T cells or B cells characterized in bulk and single-cell sequencing data. The resurgence of interest in T cell and B cell epitopes emphasizes the need to catalog all cancer epitope-related data linked to the biological, immunological, and clinical contexts, and most importantly, making this information freely available to the scientific community in a user-friendly format. In parallel, there is also a need to develop resources for epitope prediction and analysis tools that provide researchers access to predictive strategies and provide objective evaluations of their performance. For example, such tools should enable researchers to identify epitopes that can be effectively used for immunotherapy or in defining biomarkers to predict the outcome of checkpoint blockade therapies. We present here a detailed vision, blueprint, and work plan for the development of a new resource, the C ancer E pitope D atabase and A nalysis R esource (CEDAR). CEDAR will provide a freely accessible, comprehensive collection of cancer epitope and receptor data curated from the literature and provide easily accessible epitope and T cell/B cell target prediction and analysis tools. The curated cancer epitope data will provide a transparent benchmark dataset that can be used to assess how well prediction tools perform and to develop new prediction tools relevant to the cancer research community.

Continued discoveries of negative regulators of inflammatory signaling provide detailed molecular insights into peripheral tolerance and anti-tumor immunity. Accumulating evidence indicates that peripheral tolerance is maintained at multiple levels of immune responses by negative regulators of proinflammatory signaling, soluble anti-inflammatory factors, inhibitory surface receptors & ligands, and regulatory cell subsets. This review provides a global overview of these regulatory machineries that work in concert to maintain peripheral tolerance at cellular and host levels, focusing on the direct and indirect regulation of T cells. The recent success of checkpoint blockade immunotherapy (CBI) has initiated a dramatic shift in the paradigm of cancer treatment. Unprecedented responses to CBI have highlighted the central role of T cells in both anti-tumor immunity and peripheral tolerance and underscored the importance of T cell exhaustion in cancer. We discuss the therapeutic implications of modulating the negative regulators of T cell function for tumor immunotherapy with an emphasis on inhibitory surface receptors & ligands-central players in T cell exhaustion and targets of checkpoint blockade immunotherapies. We then introduce a Threshold Model for Immune Activation-the concept that these regulatory mechanisms contribute to defining a set threshold of immunogenic (proinflammatory) signaling required to elicit an anti-tumor or autoimmune response. We demonstrate the value of the Threshold Model in understanding clinical responses and immune related adverse events in the context of peripheral tolerance, tumor immunity, and the era of Checkpoint Blockade Immunotherapy.

Bcl-6 and Blimp-1 have recently been identified as key transcriptional regulators of effector and memory differentiation in CD4 + T cells and CD8 + T cells. Bcl-6 and Blimp-1 were previously known to be critical regulators of effector and memory differentiation of B lymphocytes. The new findings unexpectedly point to the Bcl-6 and Blimp-1 regulatory axis as a ubiquitous mechanism for controlling effector and memory lymphocyte differentiation and function. Bcl-6 and Blimp-1 are antagonistic transcription factors and can function as a self-reinforcing genetic switch for cell-fate decisions. However, their influences in different lymphocytes are complex. Here we review and examine the commonalities and differences in the functions of these transcription factors in CD4 + follicular helper T FH lymphocytes, effector CD8 + T lymphocytes and B lymphocytes.

The generation of CD8 + T cell memory requires both CD4 + T cells and dendritic cells. Schoenberger et al . show that autocrine production of interleukin 2 by licensed CD8 + T cells is also crucial. Two competing theories have been put forward to explain the role of CD4 + T cells in priming CD8 + memory T cells: one proposes paracrine secretion of interleukin 2 (IL-2); the other proposes the activation of antigen-presenting cells (APCs) via the costimulatory molecule CD40 and its ligand CD40L. We investigated the requirement for IL-2 by the relevant three cell types in vivo and found that CD8 + T cells, rather than CD4 + T cells or dendritic cells (DCs), produced the IL-2 necessary for CD8 + T cell memory. Il2 −/− CD4 + T cells were able to provide help only if their ability to transmit signals via CD40L was intact. Our findings reconcile contradictory elements implicit in each model noted above by showing that CD4 + T cells activate APCs through a CD40L-dependent mechanism to enable autocrine production of IL-2 in CD8 + memory T cells.

BackgroundCD4+ T cells play a critical role in the positive and negative regulation of cellular immunity through the many functional subsets they comprise. The progressive growth of immunogenic tumors which nonetheless generate mutation-specific T cells suggests that effective immune control may be avoided or suppressed at the level of the neoantigen-specific CD4+ T-cell response. Despite their importance, little is known about the ontogeny, architecture, and development of the CD4+ NeoAg-specific repertoire induced by progressively growing tumor.MethodsWe used a tetramer specific for a validated neoantigen, CTLCH129>Q/I-Ak, to characterize the ontogeny of natural CD4+ T-cell responses to an aggressive and poorly immunogenic major histocompatibility complex class II-deficient tumor, squamous cell carcinoma VII (SCC VII), during progressive growth or following therapeutic peptide vaccination using a combination of flow cytometry, single-cell genomics, and T-cell receptor (TCR) gene engineering.ResultsWe find that the natural CD4+ T-cell response to a growing tumor is phenotypically and functionally diverse, with distinct subsets including type 1 helper, T follicular helper-like, and regulatory T cell (Treg) lineages appearing as early as 9 days after tumor implantation. Therapeutic vaccination using the CLTCH129>Q peptide in adjuvant plus α-programmed cell death protein-1 reduces the frequency of CLTCH129>Q-specific Treg in both tumor and tumor-draining lymph node. Single-cell transcriptomic analysis of CLTC-specific CD4+ T cells recapitulated and extended the diversity of the response, with TCRs of varying affinity found within each functional subset. The TCR affinity differences did not strictly correlate with function, however, as even the lowest affinity TCRs isolated from Treg can mediate therapeutic efficacy against established tumors in the setting of adoptive cellular therapy (ACT).ConclusionsThese findings offer unprecedented insight into the functional diversity of a natural neoantigen-specific CD4+ T-cell response and show how immunotherapeutic intervention influences the phenotype, magnitude, and efficacy of the antitumor immune response. This information could lead to new approaches to immune monitoring in the clinical setting of checkpoint blockade immunotherapy and cancer vaccines. Furthermore, we show that Treg can be a potent source of TCRs that can mediate therapeutic benefit in the setting of ACT.