Abstract
Immunological tolerance has evolved to curtail immune responses against self-antigens and prevent autoimmunity. One mechanism that contributes to immunological tolerance is the expression of inhibitory receptors by lymphocytes that signal to dampen immune responses during the course of an infection and to prevent immune-mediated collateral damage to the host. The understanding that tumors exploit these physiological mechanisms to avoid elimination has led to remarkable, but limited, success in the treatment of cancer through the use of biologics that interfere with the ability of cancers to suppress immune function. This therapy, based on the understanding of how T lymphocytes are normally activated and suppressed, has led to the development of therapeutic blocking antibodies, referred to as immune checkpoint blockade, which either directly or indirectly promote the activation of CD8 T cells to eradicate cancer. Here, we highlight the distinct signaling mechanisms, timing and location of inhibition used by the CTLA-4 and PD-1 inhibitory receptors compared to a novel inhibitory signaling axis comprised of the bioactive lipid, lysophosphatidic acid (LPA), signaling via the LPA5 receptor expressed by CD8 T cells. Importantly, abundant evidence indicates that an LPA-LPA5 signaling axis is also exploited by diverse cancers to suppress T cell activation and function. Clearly, a thorough molecular and biochemical understanding of how diverse T cell inhibitory receptors signal to suppress T cell antigen receptor signaling and function will be important to inform the choice of which complimentary checkpoint blockade modalities might be used for a given cancer.
Highlights
Lipid biology in the context of tumor immunity remains vastly unexplored
As lysophosphatidic acid (LPA) is found systemically, and in all tissues, we speculate mechanisms of suppression mediated by LPA receptor (LPAR) are similar to CTLA and PD-1 in inhibiting T cell antigen receptor (TCR) signaling, yet via distinct signaling pathways
As tumors can produce LPA at higher concentrations than adjacent tissue, this tumor-derived LPA inhibits T cell effector function representing a checkpoint in T cell function similar to that mediated by CTLA4 and PD-1
Summary
Lipid biology in the context of tumor immunity remains vastly unexplored. its role in modulating inflammation has been used for centuries [1], which has led to pharmaceutical development of nonsteroidal anti-inflammatory drugs (NSAIDs), like COX-2 inhibitors, that inhibit the generation of prostaglandin and thromboxane lipids. As LPA is found systemically, and in all tissues, we speculate mechanisms of suppression mediated by LPARs are similar to CTLA and PD-1 in inhibiting T cell antigen receptor (TCR) signaling, yet via distinct signaling pathways. Despite discrepancies in the described mechanism(s) of PD-1 inhibitory action, PD-1 blockade has enjoyed major success in the clinic This is because a major ligand for PD-1 is PD-L1, whose expression is upregulated by diverse tumors in response to IFNg. when examined, ~98% of PD-L1 expressing melanocytes were co-localized with T cells as opposed to minimal co-localization of T cells with PD-L1-negative tumor cells, suggesting tumor cells express PD-L1 in response to infiltrating T cells [21]. Ongoing and new research has identified novel protein inhibitory receptors and below we further describe a lipid that signals via a cognate Gprotein coupled receptor (GPCR) to deliver suppressive signals to CD8 T cells and which negatively-regulate T cell function
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