Stimulation of chemotherapy-induced immunity by targeting IL-6 in the tumor microenvironment

Abstract

Tumor formation and progression involves the growth and co-evolution of neoplastic cells in combination with microenvironmental stromal components. Transformed tumor cells initiate crucial changes in healthy tissues that convert their environment into one that supports and furthers cancer development. Consequently, heterogenous cell types within tumors and context dependent factors can influence and shape the therapeutic responses of these diseases. These interactions promote outgrowth of therapy-refractory malignancies, which are a recurrent and challenging problem when treating cancer patients in the clinic.

One of the most effective emerging approaches to safeguard patients from cancer recurrence is the stimulation and mobilization of the immune system against tumor cells. To this end, preclinical studies of a group of cytostatic and genotoxic agents has shown that these drugs exert their effects on cancer cells by, in part, boosting the functions of immune cells. However, the vast majority of these agents do not effectively engage the immune system when used as therapies for cancer patients. Activation of innate and adaptive immune responses against cancers rely on cell-to-cell communications regulated by cytokines. These soluble factors can also generate anti-inflammatory responses depending on their concentration and timing of exposure. Thus, detrimental immunosuppressive activity promoted by cytokines is one of the context-dependent factors that inhibit tumor-specific responses.

In my thesis, using an immune-competent mouse model of B-cell acute lymphoblastic leukemia, we describe how the microenvironmentally derived cytokine IL-6 inhibits anticancer immune responses generated by chemotherapy treatment. Specifically, we demonstrate that absence of IL-6 from tumor microenvironments leads to enhanced T-lymphocyte responses that culminate in the generation of long-term immunologic memory. These findings reveal one of the mechanisms by which microenvironmental changes brought upon by tumor cells result in therapy resistance and disease recurrence. Therefore, we present supporting evidence that unravelling the therapeutic potential of IL-6 pathway inhibition in combination with immune-stimulating therapies could improve care and treatment for various oncological indications.