TCR-engineered neoantigen-specific CD4+ T cells mediate immunotherapy of a class II-negative murine squamous cell carcinoma

Abstract

The expansion of neoantigen (NeoAg)-specific T cells often accompanies clinical responses to immunotherapies such as immune checkpoint blockade (ICB), adoptive cellular therapy (ACT), and personalized cancer vaccines (PCV), highlighting their importance for antitumor immunity. While the functions of NeoAg-specific CD8+ T cells have been characterized, the role of NeoAg-specific CD4+ T cells is less well understood. To study the antitumor mechanisms of NeoAg-specific CD4+ T cells, we sorted single CD4+ T cells specific for a mutated clathrin heavy chain epitope (Cltc H129Q) expressed by the murine squamous cell carcinoma VII (SCC VII) tumor. T cell receptor (TCR) sequencing analysis revealed the presence of four distinct TCR clonotypes and expression of these TCRs in primary cells was sufficient to confer preferential recognition of Cltc H129Q as compared to the corresponding wildtype Cltc epitope. Despite differences in TCR avidity, both low and high avidity CD4+ T cells were capable of proliferating to similar degrees in response to tumor antigen in vivo and enhancing primary tumor immunity in a CD8+ T cell- and CD40L-dependent manner. ACT with Cltc H129Q specific CD4+ T cells also synergized with cyclophosphamide treatment to reduce disease burden in mice with established tumors. Overall, these findings illuminate the mechanistic role of NeoAg-specific CD4+ T cells in tumor immunity, provide insights into the impact of TCR avidity on the helper functions of CD4+ T cells, and highlight the therapeutic potential of ACT with TCR-engineered CD4+ T cells.

Necroptosis Stimulates Interferon-Mediated Protective Anti-Tumor Immunity

“…Our results differ from the traditional view that ICD mainly stimulates DC cross-priming of CD8 + T cells to promote tumor protection (27,28). CD4 + T cells have been described to contribute to anti-tumor immunity through a variety of mechanisms including direct killing of tumor cells, augmenting the tumor microenvironment through local secretion of effector cytokines, and providing help to CD8 + T cells (29)(30)(31)(32)(33). Our study complement prior reports that necroptotic signaling in tumors (34) and cardiac allografts (35) can bolster effector CD4 + T cell responses.…”

Homologous-Magnetic Dual-Targeted Metal-Organic Framework to Improve the Anti-Hepatocellular Carcinoma Efficacy of PD-1 Inhibitor

“…Among different subgroups of TILs, CD8 + TILs play a crucial role in eliminating tumour cells, whereas CD4 + TILs contribute to anti-tumour effects by assisting CD8 + TILs. [48][49][50] On quantifying CD8 + and CD4 + TIL subpopulations, we found that the abundance of CD8 + TILs (4.81-fold, p < 0.01) and CD4 + TILs (4.04fold, p < 0.01) was signi cantly higher in the combination group than in the model group (Figure . 6H, Figure. S7).…”

Thetis cells induce food-specific Treg cell differentiation and oral tolerance

“…A wealth of studies examining CD8 T cell differentiation have demonstrated the development of TCF1 hi 'stem-like' memory T cells that sustain CD8 effectors in settings of chronic antigen availability 18 . Analogous populations of CD4 stem cell memory T cells have recently been identified in lymph nodes during transplantation, tumorigenesis and autoimmunity [19][20][21][22] . Since continuous dietary exposure provides chronic antigen stimulation, it seems likely that food-specific T cells would be sustained by such progenitors.…”