Abstract
Accumulating evidence indicates that inflammation plays a critical role in cancer development; however, mechanisms of immunosuppression hinder productive anti-tumor immunity to limit immunopathology. Tumor-specific cytotoxic T lymphocyte (CTL) dysfunction or exhaustion by upregulating inhibitory receptors such as programmed cell death 1 (PD-1) in tumor-bearing hosts is one such mechanism. Identification and blockade of the pathways that induce CTL dysfunction has been shown to partially restore CTL function in tumor-bearing hosts. Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme for prostanoid biosynthesis, including prostaglandin E2 (PGE2), and plays a key role in both inflammation and cancer. The disruption of COX2/PGE2 signaling using COX2 inhibitors or PGE2 receptors EP2 and EP4 antagonists, combined with anti-PD-1 blockade was therapeutic in terms of improving eradication of tumors and augmenting the numbers of functional tumor-specific CTLs. Thus, COX2/PGE2 axis inhibition is a promising adjunct therapy to PD-1 blockade for immune-based therapies in cancer.
Highlights
Tumor-specific cytotoxic T lyphocytes (CTLs) is considered to manifest the host immunologic response to tumor antigens inside the tumor tissue micro-environment [1], another process that is indispensable is host-driven immune depression, which attenuates anti-tumor immunological reactions [2]
Given the known pleiotropic suppressive effects of the COX2/prostaglandin E2 (PGE2) axis on tumor-specific CTLs immunity, and the documented ability of blockade of tumor-associated COX2 to skew toward a type-1 cytokine response [25, 26], we anticipated a negative correlation between COX2 and the local development CTL cells associated with the cancer microenvironment
We investigated the involvement of PGE2 in the initial primary of naïve CD8+ T cells (Supplementary Figure 2) and development of tumor-derived CTLs associated with the cancer microenvironment
Summary
Tumor-specific cytotoxic T lyphocytes (CTLs) is considered to manifest the host immunologic response to tumor antigens inside the tumor tissue micro-environment [1], another process that is indispensable is host-driven immune depression, which attenuates anti-tumor immunological reactions [2]. As shown in infectious disease models, continuous challenge of chronic antigen often result in ineffective tumor-specific CTLs responses due to functional exhaustion and may lose their ability to produce key cytokines that play a pivotal role in maintenance of CTLs memory [3, 4]. A considerable amount of evidence has recently revealed that the expression of these receptors plays an important role in modulating multiple functional aspects of the exhaustion of CTLs [7, 8]. This expression may result in physical reduction of certain tumor-specific CTL populations [9]. It will be important to www.impactjournals.com/oncotarget identify the factors that govern CTL exhaustion to develop more efficient treatments
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