The presence of tumor-infiltrating effector T cells is considered the most predictive biomarker for clinical benefit in response to immunotherapies. IL-15 is a cytokine important for the proliferation, activation and mobilization of lymphocytes, including natural killer and CD8+T cells. We have previously shown that bioactive IL-15 in vivo comprises a non-dissociating complex of the IL-15 chain with the IL-15 receptor alpha chain that are together termed heterodimeric IL-15 (hetIL-15). Several preclinical models have indicated the ability of hetIL-15 to enhance the response of the immune system against cancer.
Repeated injections of hetIL-15 in tumor-bearing mice were effective in delaying tumor growth in the MC38 colon carcinoma, TC-1 cervical carcinoma and B16 melanoma models. The beneficial effects of hetIL-15 therapy included a significantly reduced onset of lung metastasis in 4T1 breast cancer-bearing mice. The combination of hetIL-15 and adoptive cell transfer of melanoma specific Pmel-1 cells showed anti-tumor efficacy in B16-bearing mice in absence of lymphodepletion, a finding that may have clinical applications. Analysis by flow cytometry and multi-color immunohistochemistry showed that hetIL-15 administration induced a significant increase of tumor infiltration and persistence of CD8+ T cells, including tumor specific T cells, and resulted in an increased CD8+/Treg ratio. Importantly, hetIL-15 treatment led to preferential enrichment of adoptively transferred tumor-specific CD8+T cells in the B16 tumor in an antigen-dependent manner. Tumor-resident CD8+ T cells showed features of activated effector cells and were characterized by increased proliferation (Ki67+) and high cytotoxic potential (Granzyme B+).
In conclusion, our results showed that hetIL-15 administration may be a general method to enhance T cell entry in non-inflamed tumors, increasing the success rate of immunotherapy interventions. Preclinical cancer studies support the use of hetIL-15 in tumor immunotherapy approaches to promote the development of anti-tumor responses by favoring effector over regulatory cells.