Decreased cytotoxic T cells and TCR clonality in organ transplant recipients with squamous cell carcinoma

Area of Science:

• Immunology
• Oncology
• Dermatology

Background:

• Cutaneous squamous cell carcinoma (cSCC) presents unique challenges in organ transplant recipients (OTR) due to their immunosuppressed state.
• Understanding the tumor-infiltrating lymphocyte (TIL) landscape in OTR is crucial for managing cSCC.
• Existing research lacks detailed characterization of T-cell responses in OTR-cSCC compared to immune-competent individuals.

Purpose of the Study:

• To investigate and compare the T-cell landscape in cSCC tumors between immune-competent (IC) individuals and OTR.
• To develop and apply a novel analytical method for defining TIL phenotype using single-cell sequencing.
• To identify potential differences in T-cell receptor (TCR) clonotypes and antigen recognition in OTR-cSCC.

Main Methods:

• Utilized single-cell TCR sequencing and gene expression data to analyze TILs.
• Developed a novel barcoding method for CD8+ T-cells to obtain both gene expression and TCR sequences.
• Compared TIL phenotype, TCR repertoire diversity, and antigen specificity between cSCC in IC patients and TSCC in OTR.

Main Results:

• TSCC in OTR showed reduced proportions of cytotoxic and naïve TILs, with similar numbers of regulatory TILs compared to IC patients.
• TILs from OTR exhibited fewer and more heterogeneous TCR clonotypes.
• A significant portion (24%) of top TCR clonotypes in OTR corresponded to putative neoantigens, alongside known antigens.

Conclusions:

• OTR exhibit a distinct T-cell tumor microenvironment in cSCC, characterized by diminished cytotoxic T-cell populations.
• The observed reduction in cytotoxic TILs may contribute to the increased incidence of cSCC events in OTR.
• This research provides a foundational understanding of T-cell responses and antigen recognition in OTR-cSCC, paving the way for personalized therapeutic strategies.