PD-1 and ICOS coexpression identifies tumor-reactive CD4+ T cells in human solid tumors

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• CD4+ T helper (Th) cells are crucial for immune responses, but their specific roles in antitumor immunity are not fully understood.
• Identifying specific Th cell subsets involved in anti-cancer immunity is essential for developing effective immunotherapies.
• Previous research has not clearly defined the CD4+ Th cell populations directly involved in recognizing and attacking tumor cells.

Purpose of the Study:

• To identify and characterize CD4+ Th cells that infiltrate and actively participate in the antitumor immune response.
• To investigate the phenotype, location, and antigen recognition capabilities of these tumor-specific CD4+ Th cells.
• To establish methods for isolating tumor-reactive CD4+ Th cells for further study and potential therapeutic applications.

Main Methods:

• Analysis of immune cell infiltrates in head and neck squamous cell carcinoma and colorectal cancer tissues.
• Phenotypic characterization of CD4+ Th cells, including co-expression of programmed cell death 1 (PD-1) and ICOS (inducible T cell costimulator).
• Assessment of T cell receptor repertoire, proliferation, and antigen recognition of identified CD4+ Th cells.

Main Results:

• A distinct subset of CD4+ Th cells, co-expressing PD-1 and ICOS, was identified within tumors, separate from regulatory T cells (Tregs).
• These tumor-infiltrating lymphocyte (TIL) CD4+ Th cells exhibited a tissue-resident memory phenotype, localized in MHC class II-rich areas, and proliferated locally.
• The T cell receptor repertoire of these PD-1+ICOS+ CD4+ Th TILs was oligoclonal and recognized both tumor-associated antigens and tumor-specific neoantigens.

Conclusions:

• A novel population of tumor-reactive CD4+ Th cells (PD-1+ICOS+) has been identified within the tumor microenvironment.
• These cells possess characteristics suggesting local antigen recognition and a role in antitumor immunity.
• The findings provide a method for isolating these cells ex vivo, paving the way for understanding their function and improving adoptive T cell therapies for cancer.