Progressing malignancies establish robust immunosuppressive networks that operate both systemically and locally. In particular, as tumors escape immunosurveillance, they recruit increasing amounts of myeloid and lymphoid cells that exert pronounced immunosuppressive effects. These cells not only prevent the natural recognition of growing neoplasms by the immune system, but also inhibit anticancer immune responses elicited by chemo-, radio- and immuno therapeutic interventions. Throughout the past decade, multiple strategies have been devised to counteract the accumulation or activation of tumor-infiltrating immunosuppressive cells for therapeutic purposes. Here, we review recent preclinical and clinical advances on the use of small molecules that target the immunological tumor microenvironment for cancer therapy. These agents include inhibitors of indoleamine 2,3-dioxigenase 1 (IDO1), prostaglandin E2, and specific cytokine receptors, as well as modulators of intratumoral purinergic signaling and arginine metabolism.

Department of Women's and Children's Health Karolinska University Hospital Stockholm Sweden

Dept of Immunology 2nd Faculty of Medicine and University Hospital Motol Charles University Prague Czech Republic

Equipe 11 labellisée par la Ligue Nationale contre le Cancer Centre de Recherche des Cordeliers Paris France

Equipe 13 Centre de Recherche des Cordeliers Paris France

Group of Immune receptors of the Innate and Adaptive System Institut d'Investigacions Biomédiques August Pi i Sunyer Barcelona Spain

Gustave Roussy Cancer Campus Villejuif France

INSERM U1015 CICBT507 Villejuif France

INSERM U1138 Paris France

INSERM U970 Paris France

Laboratory of Integrative Cancer Immunology Centre de Recherche des Cordeliers Paris France

Metabolomics and Cell Biology Platforms Gustave Roussy Cancer Campus Villejuif France

Paris Cardiovascular Research Center Paris France

Pôle de Biologie Hôpital Européen Georges Pompidou AP HP Paris France

Service d'Immunologie Biologique Hôpital Européen Georges Pompidou AP HP Paris France

Sotio Prague Czech Republic

Université Paris Descartes Paris 5 Sorbonne Paris Cité Paris France

Université Pierre et Marie Curie Paris 6 Paris France

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$a Progressing malignancies establish robust immunosuppressive networks that operate both systemically and locally. In particular, as tumors escape immunosurveillance, they recruit increasing amounts of myeloid and lymphoid cells that exert pronounced immunosuppressive effects. These cells not only prevent the natural recognition of growing neoplasms by the immune system, but also inhibit anticancer immune responses elicited by chemo-, radio- and immuno therapeutic interventions. Throughout the past decade, multiple strategies have been devised to counteract the accumulation or activation of tumor-infiltrating immunosuppressive cells for therapeutic purposes. Here, we review recent preclinical and clinical advances on the use of small molecules that target the immunological tumor microenvironment for cancer therapy. These agents include inhibitors of indoleamine 2,3-dioxigenase 1 (IDO1), prostaglandin E2, and specific cytokine receptors, as well as modulators of intratumoral purinergic signaling and arginine metabolism.

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