Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells.
Active suppression of tumor-specific T lymphocytes can limit the efficacy of immune surveillance and immunotherapy. While tumor-recruited CD11b+ myeloid cells are known mediators of tumor-associated immune dysfunction, the true nature of these suppressive cells and the fine biochemical pathways governing their immunosuppressive activity remain elusive. Here we describe a population of circulating CD11b+IL-4 receptor alpha+ (CD11b+IL-4Ralpha+), inflammatory-type monocytes that is elicited by growing tumors and activated by IFN-gamma released from T lymphocytes. CD11b+IL-4Ralpha+ cells produced IL-13 and IFN-gamma and integrated the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits were active in CD11b+ cells present within the tumor microenvironment. These suppressor cells challenge the current idea that tumor-conditioned immunosuppressive monocytes/macrophages are alternatively activated. Moreover, our data show how the inflammatory response elicited by tumors had detrimental effects on the adaptive immune system and suggest novel approaches for the treatment of tumor-induced immune dysfunctions.
Gallina
Giovanna
G
Istituto Oncologico Veneto, Padua, Italy.
Dolcetti
Luigi
L
Serafini
Paolo
P
De Santo
Carmela
C
Marigo
Ilaria
I
Colombo
Mario P
MP
Basso
Giuseppe
G
Brombacher
Frank
F
Borrello
Ivan
I
Zanovello
Paola
P
Bicciato
Silvio
S
Bronte
Vincenzo
V
D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D039481:CD11b Antigen / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D007111:Immunity, Cellular / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018793:Interleukin-13 / Q000378:metabolism / Q000494:pharmacology; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D053662:Interleukin-4 Receptor alpha Subunit
D001119:Arginase; D039481:CD11b Antigen; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D018793:Interleukin-13; D015847:Interleukin-4; D052247:Nitric Oxide Synthase Type II; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C496317:Nos2 protein, mouse