Exploring immunotherapeutic targets in the tumor microenvironment

The immune system has developed along with the evolution of increasingly complex cellular organisms to sustain homeostasis and protect from threats. Cancer, a detrimental side effect of increasing organismic complexity, typically sequesters the immune system and hijacks its functions for its own prosperity. Cancer immunotherapy aims to harness the intrinsic potential of the immune system for the therapeutic benefit of cancer patients. The focus of this thesis is to identify and evaluate new immunotherapeutic targets in the tumor microenvironment, which can be modulated to restrict tumor growth and metastasis.

Paper I describes a novel mechanism of interaction between marginal zone macrophages (MZMs) and marginal zone B cells (MZBs) in the spleen, which can be modulated by antibodies (Abs) to scavenger receptor MARCO on MZMs. This study demonstrates that MARCO targeting diminishes antigen (Ag) uptake by MZBs, which results in reduced Ag deposition in the splenic follicles. As anti-MARCO Abs can also be found in systemic lupus erythematosus (SLE), this interaction may affect subsequent adaptive immune responses to both self- and foreign antigen.

Paper II identifies MARCO as a specific marker for a tumor-promoting macrophage subtype in the tumor microenvironment of mammary carcinoma, melanoma and colon carcinoma tumor models. Targeting MARCO on tumor-associated macrophages (TAMs) by Abs, inhibits tumor growth and metastasis and reprograms TAMs to an anti-tumor phenotype. Treatment with anti-MARCO mAbs in combination with checkpoint inhibitor, anti-CTLA-4 ab, may provide a promising approach for cancer immunotherary with clinical relevance for human breast cancer and melanoma.

Paper III reveals the molecular mechanism through which tumor cells imitate immune cells, during epithelial-mesenchymal transition (EMT), prompting their targeted metastasis through the lymphatics. This study demonstrates that TGF-β, a known inducer of EMT, regulates the chemotactic axis CCR7/CCL21, directing preferential lymphatic dissemination of breast cancer cells.

Paper IV evaluates dendritic cell-derived exosomes in a vaccination approach to reactivate adaptive anti-tumor responses. This study shows that dendritic cell-derived CD1d expressing exosomes loaded with α-Galactosylceramide (α-GalCer) can sensitize NKT cells and lead to subsequent activation of B cell and effector T cell responses, restricting tumor growth.

In summary, the work presented in this thesis describes novel targets in the tumor microenvironment that can be used in immunotherapeutic approaches to re-activate endogenous mechanisms of innate and adaptive immunity against cancer. Additionally, it gives new insight into gene regulatory pathways controlling metastatic tumor spread, as well as utilizes custom designed biological molecules in anti-tumor vaccination strategies. Increasing our understanding of the intricate mechanisms regulating the immunosuppressive tumor microenvironment will reveal new knowledge and novel targets that can contribute to the design of prospective cancer immunotherapies.

List of scientific papers

I. Prokopec K, Georgoudaki AM, Sohn S, Wermeling F, Grönlund H, Lindh E, Carroll MC, Karlsson MCI Marginal zone macrophages regulate antigen transport by B cells to the follicle in the spleen via CD21 [Submitted]

II. Georgoudaki AM, Prokopec K, Boura V, Hellqvist E, Sohn S, Östling J, Dahan R, Harris RA, Rantalainen M, Klevebring D, Sund M, Egyhazi Brage S, Fuxe J, Rolny C, Li F, Ravetch JV, Karlsson MCI Reprogramming tumor associated macrophages by antibody targeting inhibits cancer progression and metastasis [Submitted]

III. Pang MF, Georgoudaki AM, Lambut L, Johansson J, Tabor V, Hagikura K, Jin Y, Jansson M, Alexander JS, Nelson CM, Jakobsson L, Betsholtz C, Sund M, Karlsson MCI, Fuxe J TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21- mediated chemotaxis Oncogene, 2015 May 11.
https://doi.org/10.1038/onc.2015.133

IV. Gehrmann U, Hiltbrünner S, Georgoudaki AM, Karlsson MCI, Näslund TI, Gabrielsson S Synergistic induction of adaptive antitumor immunity by codelivery of antigen with α-galactosylceramide on exosomes Cancer Research, 2013 Jul 1;73(13):3865-76
https://doi.org/10.1158/0008-5472.CAN-12-3918