Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy

Area of Science:

• Oncology
• Immunology
• Cancer Research

Background:

• Chemoradiotherapy (CRT) is a common cancer treatment, most effective with an anti-tumoral immune response.
• CRT can also induce immunosuppressive mechanisms that limit its effectiveness.
• Modulating the immune microenvironment is crucial to maximize CRT's immune-stimulating effects.

Purpose of the Study:

• To develop and evaluate a combination therapy for HPV-associated head and neck squamous cell carcinoma (HNSCC).
• To investigate the effects of combining CRT with immunomodulatory drugs cyclophosphamide (CTX) and L-NIL on the tumor immune microenvironment and treatment efficacy.

Main Methods:

• Utilized a preclinical model of HPV-HNSCC in mice.
• Administered fractionated radiation and weekly cisplatin (CRT).
• Compared CRT alone with CRT combined with CTX/L-NIL using flow cytometry, multiplex immunofluorescence, and gene expression profiling.

Main Results:

• Combination therapy favorably remodeled the tumor myeloid immune microenvironment, increasing anti-tumor immune cells (monocytes, M1-like macrophages) and decreasing immunosuppressive cells (MDSCs).
• Improved intratumoral T cell infiltration and tumor antigen specificity, evidenced by a 31.8-fold increase in the CD8+ T cell/regulatory T cell ratio.
• Combination treatment significantly enhanced CRT efficacy, leading to rejection of 21% of established tumors in a CD8-dependent manner.

Conclusions:

• Modulating the tumor immune microenvironment with CTX/L-NIL enhances susceptibility of treatment-refractory tumors to CRT.
• Combining immune microenvironment modulation with CRT is a translationally relevant approach to improve CRT efficacy via enhanced immune activation.