Inhibition of SIRPα in dendritic cells potentiates potent antitumor immunity

Abstract

Despite their central function in tumor immunity, dendritic cells (DCs) can respond to inhibitory signals and become tolerogenic, curtailing T cell responses in vivo. Here, we provide the evidence for an inhibitory function of signal regulatory protein (SIRP) a in DC survival and activation. In tumors from human liver cancer patients, infiltrative DCs expressed elevated levels of SIRPa, which is correlated with the induction of immune tolerance within the tumors. Silencing of SIRPa resulted in a significant increase in the longevity of antigen-pulsed DCs in the draining lymph nodes. In addition, SIRPa controls the activation and output of DCs. Silencing of DC-expressed SIRPa induced spontaneous and enhanced production of IL12 and costimulatory molecules, resulting in more potent cytotoxic T lymphocyte responses, including the eradication of previously established solid tumors. SIRPa exerted such effects, at least in part, via the association and sequestration of p85 subunit of PI3K. Thus, SIRPa is a critical regulator of DC lifespan and activity, and its inhibition might improve the clinical efficacy of DC-based tumor vaccines.

The CD47‐SIRPα signaling axis as an innate immune checkpoint in cancer

“…Furthermore, the authors showed that the therapeutic effect of CD47 blocking antibody treatment was accomplished through STING sensing of DNA within the DC and the ability to produce type I IFN . These results are supported by a recent report in which the silencing of SIRPα expression in adoptively transferred antigen‐pulsed dendritic cells was also shown to promote cytotoxic anti‐cancer T cell responses . The exact mechanism(s) by which CD47‐SIRPα interactions control the induction of tumor‐specific cytotoxic T cell responses is not known, but it seems feasible that an enhanced tumor material uptake by dendritic cells followed by improved antigen presentation and/or co‐stimulation contributes to this (Figure B).…”

Genome variation across cancers scales with tissue stiffness – An invasion-mutation mechanism and implications for immune cell infiltration

“…An alternative vaccination approach exploits MHC class II molecules expressed by macrophages [14,15]. Like MHC I, MHC II presents peptide fragments at the cell surface.…”

“…The immune system is therefore not activated by MHC II presentation of neo-antigens [86]. However, macrophages have long been engineered ex vivo for anti-cancer purposes and can be made to express patient-specific cancer neo-antigen peptide sequences loaded into MHC II [15]. Upon injection back into the patient, these engineered macrophages activate the immune system against cancer cells that display the special peptide sequence.…”

“…Tumor associated macrophages (TAMs) can, through inhibition of CD47, phagocytose cancer cells [91], and then present neo-antigens from those cells to activate the adaptive immune system [86,92]. However, TAMs promote tumor growth, are weakly phagocytic even with CD47 disruption, and have low MHC II expression, which hinders their ability to activate an adaptive immune response [15,93,94]. A cell therapy approach using marrow-derived monocytes and macrophages could be an alternative, as these cells have low SIRPα (i.e.…”

“…A moonshot-scale effort now seeks to employ neo-antigens in various immunotherapy approaches. Some therapies use engineered T-cells to target neo-antigens on the cancer cell membrane [12], while other therapies exploit the major histocompatibility complex (MHC)—class I and class II—to target nuclear and cytoplasmic neo-antigens [13–15]. Monocytes and macrophages are the focus here and are particularly interesting for targeting to neo-antigens because these phagocytic cells exhibit a robust ability to infiltrate solid tissues, including tumors.…”