Tumor immunogenicity regulates host immune responses, and conventional dendritic cell type 2 uptakes the majority of tumor antigens in an orthotopic lung cancer model

TL;DR

This study shows that increasing tumor immunogenicity boosts immune responses in a mouse lung cancer model, with conventional dendritic cell type 2 playing a key role in recognizing tumor antigens.

Contribution

The study introduces a modified KP mouse model with engineered neoantigens to better understand tumor immunogenicity and dendritic cell roles in lung cancer.

Findings

The KP model expressing minOVA showed increased immune infiltration and suppressed tumor growth.

Conventional dendritic cell type 2 (cDC2) predominantly uptakes tumor neoantigens in the model.

Higher tumor immunogenicity correlates with stronger antitumor immune responses in the orthotopic lung cancer model.

Abstract

Human lung cancer carries high genetic alterations, expressing high tumor-specific neoantigens. Although orthotopic murine lung cancer models recapitulate many characteristics of human lung cancers, genetically engineered mouse models have fewer somatic mutations than human lung cancer, resulting in scarce immune cell infiltration and deficient immune responses. The endogenous mouse lung cancer model driven by Kras mutation and Trp53 deletion (KP model) has minimal immune infiltration because of a scarcity of neoantigens. Fine-tuning tumor antigenicity to trigger the appropriate level of antitumor immunity would be key to investigating immune responses against human lung cancer. We engineered the KP model to express antigens of OVA peptides (minOVA) as neoantigens along with ZsGreen, a traceable fluorescent conjugate. The KP model expressing minOVA exhibited stronger immunogenicity with higher immune cell infiltration comprised of CD8+ T cells and CD11c+ dendritic cells (DCs). Consequentially, the KP model expressing minOVA exhibits suppressed tumor growth compared to its origin. We further analyzed tumor-infiltrated DCs. The majority of ZsGreen conjugated with minOVA was observed in the conventional type 2 DCs (cDC2), where cDC1 has minimal. These data indicate that tumor immunogenicity regulates host immune responses, and tumor neoantigen is mostly recognized by cDC2 cells, which may play a critical role in initiating anti-tumor immune responses in an orthotopic murine lung cancer model.

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