Friday, April 19, 2024
4/19/2024
Abstract: More than one million cases of cutaneous squamous cell carcinoma (cSCC) are diagnosed annually in the US and approximately 4% of patients develop metastases and 2% die of cSCC; thus, a similar number of people die each year from cSCC as melanoma. Immune checkpoint inhibitors (ICI) are a new class of drugs that have transformed the therapy of multiple cancer types, but only half of cSCC patients respond to ICI treatment. ICI target receptors on T cells, such as PD-1, that are expressed after activation and function to turn off T cell responses. The response of cSCC patients to ICI demonstrates the ability of T cells to constrain cSCC growth. However, it remains unclear the extent to which CD8 and, in particular, CD4 T cells contribute to immune-mediated control of cSCC. While the focus of anti-tumor T cell responses has been on MHC class I neoantigens that elicit cytotoxic CD8 T cell responses, there is growing evidence that MHC class II neoantigens eliciting CD4 T cell responses are critical in constraining tumor growth and enhancing response to ICI. Thus, there is a critical need to understand the role of CD8 and CD4 T cells, especially the role of neoantigen-specific T cells, in controlling cSCC growth. We generated a novel physiologic cSCC transplantable model on the BALB/c background from a solar simulated light-induced invasive cSCC tumor. Preliminary data supports that T cells constrain the in vivo tumor growth in the cSCC model and that this model is sensitive to anti-PD-1 treatment. Using bioinformatic approaches with whole exome and RNA sequencing data, we have identified immunogenic MHC class I and II neoantigens predicted to elicit a T cell response based on the binding affinity and presentation of the neoantigen:MHC complex and neoantigen expression. Using melanoma patient data, our lab has previously demonstrated that these characteristics accurately predict the ability of a neoantigen to elicit a T cell response. The central hypothesis is that both neoantigen- specific CD8 and CD4 T cells contribute to immune-mediated control of cSCC growth and response to treatment with vaccination with immunogenic neoantigens alone or in combination with anti-PD-1. To address this hypothesis, we will determine the role of CD8 and CD4 T cells in controlling tumor growth, identify MHC class I and II neoantigens that elicit in vivo T cell responses, and evaluate the expression of functional and inhibitory neoantigen-specific CD8 and CD4 T cells throughout cSCC tumor growth. Then, we will vaccinate mice with dendritic cells loaded with irradiated tumor cells or immunogenic MHC class I and/or II neoantigens and compare the efficacy of these vaccination strategies in inducing CD8 and/or CD4 T cells to prevent cSCC growth and treat cSCC alone or in combination with anti-PD-1. We will demonstrate the requirement for CD8 and/or CD4 T cells through antibody depletion and adoptive transfer. The impact of this project is to 1) identify the contributions of neoantigen-specific CD8 and CD4 T cells in control of cSCC growth and 2) advance the application of personalized neoantigen vaccines to treat cSCC alone or in combination with anti-PD-1.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
