Phd thesis defense Anna Oja: Functionality of CD4+ TRM cells

Anna Oja

On June 18, Sanquin researcher Anna Oja will defend her PhD thesis at the University of Amsterdam. Her research sheds light on the functionality of CD4+ TRM, which could be targeted in novel vaccine strategies and anti-cancer immunotherapies.

Current vaccine strategies and cancer immunotherapies rely heavily on the induction of cytotoxic CD8+ T cells. CD4T cell help is required for optimal CD8+ T cell responses. Whether CD4T cells have a similar role in human tissues and cancer requires further investigation.

In this thesis, we focused on the characterization of less conventional functions of human CD4T cells in different tissue compartments and cancer. Transcription factor Hobit identifies cytotoxic CD4+ T cells that arise during primary hCMV infection.

We further defined the core signature of human lung CD4+ TRM, which display properties of CD8+ TRM and have a fast and polyfunctional recall response. Lung CD4+ TRM localize in heterogeneous patterns and consist of distinct subsets of TH1 and TH17 TRM, recognizing numerous pathogens.

NSCLC tumors also contain polyfunctional pathogen-specific CD4+ TILs with a residency phenotype and PD-1 expression distinguishes functionally distinct subsets. The abundance of CXCL13+CD4+ TILs with a residency phenotype, significantly correlates with survival and frequencies of CD8+ TIL subsets shown to be enriched for tumor-specificity. This suggests that CXCL13+CD4+ TILs are important in anti-tumor immunity and reflect a patient’s ability to form an anti-tumor response.

CD4+ TRM are also protective against coronaviruses. SARS-CoV-2 elicits a strong TH1 T cell response. COVID-19 ICU patients develop high antibody titers, but an impaired CD4+ T cell response. Furthermore, BALF of these patients contain T cells resembling circulating cells rather than TRM, suggestive of vascular leakage, altogether indicating misbalanced cellular and humoral responses in patients unable to control SARS-CoV-2 infection. Taken together, our findings shed light on the functionality of CD4+ TRM, which could be targeted in novel vaccine strategies and anti-cancer immunotherapies.

Promotor:
Prof RAW van Lier MD PhD
Co-promotores:
P Hombrink PhD
MA Nolte PhD

Venue
University of Amsterdam, Agnietenkapel (invitation only) and online.