In human and mouse lung and colorectal cancer, Kwart and He et al. identified functionally distinct tumor monocyte populations: newly recruited (CD88-Sca-1-), immunosuppressive (CD88+Sca-1-), and immunostimulatory (CD88+Sca-1+). The latter expressed genes for type-I IFN response and antigen presentation; this signature was enriched in CSCC ICB responders. Blood monocytes rapidly adopted these phenotypes in tumors, and stimulatory monocyte polarization required tumor-secreted IFNα/β and cGAS-STING activity. Overexpressing cGAS in LLC tumors increased IFN production, stimulatory monocyte polarization, and ICB efficacy.
Contributed by Alex Najibi
ABSTRACT: Monocytes are highly plastic immune cells that modulate antitumor immunity. Therefore, identifying factors that regulate tumor monocyte functions is critical for developing effective immunotherapies. Here, we determine that endogenous cancer cell-derived type I interferons (IFNs) control monocyte functional polarization. Guided by single-cell transcriptomic profiling of human and mouse tumors, we devise a strategy to distinguish and separate immunostimulatory from immunosuppressive tumor monocytes by surface CD88 and Sca-1 expression. Leveraging this approach, we show that cGAS-STING-regulated cancer cell-derived IFNs polarize immunostimulatory monocytes associated with anti-PD-1 immunotherapy response in mice. We also demonstrate that immunosuppressive monocytes convert into immunostimulatory monocytes upon cancer cell-intrinsic cGAS-STING activation. Consistently, we find that human cancer cells can produce type I IFNs that polarize monocytes, and our immunostimulatory monocyte gene signature is enriched in patient tumors that respond to anti-PD-1 immunotherapy. Our work exposes a role for cancer cell-derived IFNs in licensing monocyte functions that influence immunotherapy outcomes.
Author Info: (1) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (2) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (3) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (4) Regen
Author Info: (1) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (2) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (3) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (4) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (5) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (6) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (7) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (8) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (9) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (10) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (11) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (12) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (13) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (14) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (15) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (16) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (17) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (18) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (19) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (20) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (21) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (22) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (23) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (24) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (25) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (26) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (27) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (28) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (29) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (30) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (31) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (32) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. (33) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. Electronic address: bei.wang@regeneron.com. (34) Regeneron Pharmaceuticals, Tarrytown, NY 10591, USA. Electronic address: dimitris.skokos@regeneron.com.
