Intratumoral follicular regulatory T cells curtail anti-PD-1 treatment efficacy.
Simon EschweilerJames ClarkeCiro Ramírez-SuásteguiBharat PanwarAriel MadrigalSerena J CheeIoannis KarydisEdwin WooAiman AlzetaniSomaia ElsheikhChristopher J HanleyG J ThomasPeter S FriedmannTilman Sanchez-ElsnerFerhat AyChristian Hermann OttensmeierPandurangan VijayanandPublished in: Nature immunology (2021)
Immune-checkpoint blockade (ICB) has shown remarkable clinical success in boosting antitumor immunity. However, the breadth of its cellular targets and specific mode of action remain elusive. We find that tumor-infiltrating follicular regulatory T (TFR) cells are prevalent in tumor tissues of several cancer types. They are primarily located within tertiary lymphoid structures and exhibit superior suppressive capacity and in vivo persistence as compared with regulatory T cells, with which they share a clonal and developmental relationship. In syngeneic tumor models, anti-PD-1 treatment increases the number of tumor-infiltrating TFR cells. Both TFR cell deficiency and the depletion of TFR cells with anti-CTLA-4 before anti-PD-1 treatment improve tumor control in mice. Notably, in a cohort of 271 patients with melanoma, treatment with anti-CTLA-4 followed by anti-PD-1 at progression was associated with better a survival outcome than monotherapy with anti-PD-1 or anti-CTLA-4, anti-PD-1 followed by anti-CTLA-4 at progression or concomitant combination therapy.
Keyphrases
- regulatory t cells
- combination therapy
- induced apoptosis
- gene expression
- squamous cell carcinoma
- cell cycle arrest
- dendritic cells
- metabolic syndrome
- type diabetes
- immune response
- mass spectrometry
- cell proliferation
- stem cells
- replacement therapy
- high resolution
- endoplasmic reticulum stress
- insulin resistance
- signaling pathway
- study protocol
- free survival
- squamous cell