Immunological mechanisms of intravesical chitosan/interleukin-12 immunotherapy against murine bladder cancer

Abstract

There is a critical unmet clinical need for bladder cancer immunotherapies capable of inducing durable antitumor immunity. We have shown that four intravesical treatments with a simple co-formulation of interleukin-12 and the biopolymer chitosan not only destroy orthotopic bladder tumors, but also promote a potent long-lasting systemic immune response as evidenced through tumor-specific in vitro killing assays, complete protection from rechallenge, and abscopal antitumor responses at distant non-treated tumors. This study investigates the immunological kinetics underlying these results. We show through depletion studies that CD8+ T cells are required for initial tumor rejection, but CD4+ T cells protect against rechallenge. We also show that even a single intravesical treatment can eliminate tumors in 50% of mice with 6/9 and 7/8 mice eliminating tumors after three or four treatments respectively. We then performed immunophenotyping studies to analyze shifts in immune cell populations after each treatment within the tumor itself as well as in secondary lymphoid organs. These studies demonstrated an initial infiltration of macrophages and granulocytes followed by increased CD4+ and CD8+ effector-memory cells. This was coupled with a decreased level of regulatory T cells in peripheral lymph nodes as well as decreased myeloid-derived suppressor cell infiltration in the bladder. Taken together, these data demonstrate the ability of properly delivered interleukin-12-based therapies to engage adaptive immunity within the tumor itself as well as throughout the body and strengthen the case for clinical translation of chitosan/interleukin-12 as an intravesical treatment for bladder cancer.

Inhaled IL-10 Suppresses Lung Tumorigenesis via Abrogation of Inflammatory Macrophage–Th17 Cell Axis

“…In addition, IL-17 enhances protumorigenic cytokine production (i.e., IL-1, IL-6, and TNF-a) by myeloid cells (28,29). These activities are independent of its ability to recruit MDSC, which accumulate in advanced tumors in a size/stage-dependent manner (30,31) but are not normally found in significant numbers in early microadenomas, as shown by our data. Therefore, protumorigenic activity of IL-17 is likely mediated by multiple distinct stage-specific mechanisms.…”

Intravesical Mycobacterium brumae triggers both local and systemic immunotherapeutic responses against bladder cancer in mice

“…Despite known limitations, such as using exclusively female mice or the variability of tumor cells implanted into the bladder 27 , which could also lead to variability in the immune response generated by mycobacteria treatment, the orthotopic murine BC model is a solid, well-recognized model that provides consistent results to evaluate the immune response triggered by potential new antitumor therapies, such as IL-12 plus chitosan 28 , or the synergy of different treatments 29 . However, one drawback of our study is the low number of mice that survived until day 29 after tumor induction in the non-treated group of animals due to the high mortality rates in this group.…”

Localized Interleukin-12 for Cancer Immunotherapy

“…IL-12 is chiefly responsible for the induction and enhancement of cell-mediated immunity. Among its diverse functions, IL-12 has been shown to: (i) induce T H 1 cell differentiation; (ii) increase activation and cytotoxic capacities of T and NK cells; and (iii) inhibit or reprogram immunosuppressive cells, such as tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) (11)(12)(13)(14)(15)(16). IL-12 also induces the production of large amounts of IFNγ which itself is cytostatic/cytotoxic (17,18), anti-angiogenic (19,20) and can upregulate MHC I and II expression on tumor cells for enhanced recognition and lysis (21).…”