The role of regulatory T cells in the response to radiation therapy in head and neck cancer
Menée à l'aide d'un modèle murin de cancer de la tête et du cou, cette étude analyse le rôle des lymphocytes T régulateurs dans la réponse tumorale aux rayonnements ionisants
Background : Radioresistance represents a major problem in the treatment of head and neck cancer (HNC) patients. To improve response, understanding tumor microenvironmental factors that contribute to radiation resistance is important. Regulatory T cells (Treg) are enriched in numerous cancers and can dampen the response to radiation by creating an immune-inhibitory microenvironment. The purpose of this study was to investigate mechanisms of Treg modulation by radiation in head and neck cancer. Methods : We utilized an orthotopic mouse model of HNC. Anti-CD25 was used for Treg depletion. Image-guided radiation was delivered to a dose of 10Gy. Flow cytometry was used to analyze abundance and function of intratumoral immune cells. ELISA was performed to assess secreted factors. For immune-modulating therapies, anti-PD-L1, anti-CTLA-4 and STAT3 anti-sense oligonucleotide (ASO) were used. All statistical tests were two-sided. Results : Treatment with anti-CD25 and radiation led to tumor eradication (57.1%, 4 of 7 mice), enhanced T cell cytotoxicity compared to RT alone (CD4 Teff: RT group mean=5.37 (SD = 0.58) vs. RT +
αCD25 group mean =10.71 (SD
= 0.67), p = 0.005; CD8 Teff: RT group mean=9.98 (SD = 0.81) vs. RT +
αCD25 group mean =16.88 (SD
= 2.49), =0.01) and induced tumor antigen-specific memory response (100.0%, n = 4 mice). In contrast, radiation alone or when combined with anti-CTLA4 did not lead to durable tumor control (0.0%, n = 7 mice). STAT3 inhibition in combination with radiation, but not as single-agent, improved tumor growth delay, decreased Tregs, MDSCs and M2 macrophages and enhanced effector T cells and M1 macrophages. Experiments in nude mice inhibited the benefit of STAT3 ASO and radiation. Conclusion : We propose that STAT3 inhibition is a viable and potent therapeutic target against Tregs. Our data support the design of clinical trials integrating STAT3 ASO in the standard of care for cancer patients receiving radiation.