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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2024)

Although the efficacy of many successful immunotherapies is leveraged by T cells specific for neoantigens (NeoAg), non-self-derived antigens expressed by tumors which typically arise from point mutations, the progressive growth of tumors expressing immunogenic mutations suggests that an effective endogenous immune response is avoided or suppressed. CD4+ T cells play critical roles in the regulation of cellular immunity through the myriad subsets they can comprise but little is known about their development in response to progressive tumor growth, which limits the ability to evaluate therapeutic opportunities and efficacies. I characterized the endogenous NeoAg-specific CD4+ T cell response to a validated clathrin NeoAg (CLTCH129>Q) expressed by SCC VII, an aggressively and poorly immunogenic MHC-II-deficient tumor, using flow cytometry and a CLTCH129>Q/I-Ak tetramer throughout progressive tumor growth. We find that the natural CD4+ T cell response to a growing tumor is phenotypically and functionally diverse, with distinct subsets including type 1 helper (Th1), T follicular helper (Tfh)-like, and regulatory T cell (Treg) lineages appearing as early as 9 days after tumor inoculation. Therapeutic vaccination substantially alters the relative ratio of these subsets by sharply reducing Treg frequency among CLTCH129>Q-specific CD4+ T cells in both the tumor and tumor-draining lymph node (tdLN). Single cell transcriptomic analysis of CLTCH129>Q/I-Ak tetramer-binding CD4+ T cells recapitulated and extended the diversity of the response while permitting profiling of discovered TCRs following transduction into CD4+ T cells. TCRs of varying affinity are found within each functional subset and while affinity played no role in phenotypic fate, adoptive cellular therapies (ACT) using Th1 cells transduced with a Treg-associated TCR were still capable of mediating therapy equally well as those found on cells expressing anti-tumor phenotypes. These findings offer an 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 anti-tumor immune response.

    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2023)
    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 (CLTCH129>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 CLTCH129>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 (TSCM)-like phenotype in tumor-draining lymph nodes (tdLNs). ACT with TSCM-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.
      Cover page: Neoantigen-specific stem cell memory-like CD4+ T cells mediate CD8+ T cell-dependent immunotherapy of MHC class II-negative solid tumors.
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