TIM-4 Glycoprotein-Mediated Degradation of Dying Tumor Cells by Autophagy Leads to Reduced Antigen Presentation and Increased Immune Tolerance

Abstract

Phagocytosis of apoptotic cells by myeloid cells has been implicated in the maintenance of immune homeostasis. In this study, we found that T cell immunoglobulin- and mucin domain-containing molecule-4 (TIM-4) repressed tumor-specific immunity triggered by chemotherapy-induced tumor cell death. TIM-4 was found to be highly expressed on tumor-associated myeloid cells such as macrophages (TAMs) and dendritic cells (TADCs) and danger-associated molecular patterns (DAMPs) released from chemotherapy-damaged tumor cells induced TIM-4 on tumor-associated myeloid cells recruited from bone marrow-derived precursors. TIM-4 directly interacted with AMPKα1 and activated autophagy-mediated degradation of ingested tumors, leading to reduced antigen presentation and impaired CTL responses. Consistently, blockade of the TIM-4-AMPKα1-autophagy pathway augmented the antitumor effect of chemotherapeutics by enhancing tumor-specific CTL responses. Our finding provides insight into the immune tolerance mediated by phagocytosis of dying cells, and targeting of the TIM-4-AMPKα1 interaction constitutes a unique strategy for augmenting antitumor immunity and improving cancer chemotherapy.

CD300b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition

“…38 TIM4 does not have any signaling motif in its cytoplasmic domain but promotes engulfment of activated antigen-specific T cells, 39 as well as apoptotic cells, 11,12 via PS recognition by utilizing b1 integrins as co-receptors. 40 Deficiency of TIM4 expression is linked to reduced tolerance, 39 enhanced tumor immunity 41 and the development of autoimmunity. 12 Another PS receptor, BAI1, mediates engulfment of apoptotic cells, but unlike TIM4, directly activates downstream signaling events.…”

Blocking monoclonal antibodies of TIM proteins as orchestrators of anti-tumor immune response

“…61 However, splenic and tumor-associated macrophages were still able to engulf apoptotic cells even in the absence of TIM-4, suggesting the existence of other phagocytosis receptors expressed in these subsets of APCs. 61,62 Recent studies have identified a novel role of TIM-4 in the regulation of tumor immunity and antitumor immune responses. 62 TIM-4 plays an important role in controlling tumor-specific responses through regulation of processing and presentation of antigens derived from phagocytized apoptotic tumor cells.…”

“…61,62 Recent studies have identified a novel role of TIM-4 in the regulation of tumor immunity and antitumor immune responses. 62 TIM-4 plays an important role in controlling tumor-specific responses through regulation of processing and presentation of antigens derived from phagocytized apoptotic tumor cells. TIM-4 was found to interact with metabolic sensor AMPKa1 (adenosine monophosphate-activated protein kinase) in tumor-associated macrophages after the engulfment of apoptotic tumor cells.…”

“…TIM-4 was found to interact with metabolic sensor AMPKa1 (adenosine monophosphate-activated protein kinase) in tumor-associated macrophages after the engulfment of apoptotic tumor cells. 62 This interaction led to excessive degradation of tumor-derived antigens via autophagy-mediated mechanisms. 62 Additionally, TIM-4 may be involved in the removal of tumor antigen-specific T cells, which was previously shown in an influenza infection model.…”

Autophagosome-based strategy to monitor apparent tumor-specific CD8 T cells in patients with prostate cancer

“…Moreover, in the presence of tumor-induced suppression, function of both DCs and T cells can be hampered, further compromising elimination of tumor cells by the immune system. 4 , 5 Many immunotherapy regimens aim to convert the tolerant tumor microenvironment into an immune stimulatory one, thereby promoting tumor cell recognition and killing. 6 , 7 …”