Journal Article

Neoantigen-specific stem cell memory-like CD4+ T cells mediate CD8+ T cell-dependent immunotherapy of MHC class II-negative solid tumors

Cohen, Ezra E. W., Thota, Rukman R., Ramamoorthy Premlal, Ashmitaa Logandha, Schoenberger, Stephen P., Peters, Bjoern, Griswold, Ryan Q., Chihab, Leila, Dolina, Joseph S., Zavala, Karla Soria, Naradikian, Martin S., Brightman, Spencer E., Becker, Angelica, Miller, Aaron M.

2023

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250 / 692/699 / Adoptive immunotherapy / Animals / Antigen-presenting cells / Avidity / Biomedical and Life Sciences / Biomedicine / CD4 antigen / CD4-Positive T-Lymphocytes / CD40L protein / CD8 antigen / CD8-Positive T-Lymphocytes / Cell differentiation / Cell proliferation / Immunity / Immunological memory / Immunology / Immunotherapy / Immunotherapy, Adoptive / Infectious Diseases / Interleukin 15 / Interleukin 2 / Interleukin 7 / Lymph nodes / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Memory cells / Mice / Neoplasms - metabolism / PD-1 protein / Phenotypes / Programmed Cell Death 1 Receptor - metabolism / Receptors, Antigen, T-Cell - metabolism / Solid tumors / Squamous cell carcinoma / Stem Cells / T cell receptors / Tumor Microenvironment / Tumors