RvD5 reduced PD-1 expression on T cells and PD-L1 expression on cancer cells, thereby restoring T cell antitumor functions by delaying their differentiation into Tex, and suppresses tumor growth by dampening inflammation and delaying T cell exhaustion within the TME.
Abstract
PD-1 inhibition has revolutionized cancer therapy. However, despite the initial success of immune checkpoint inhibitors (ICIs) across several cancer types, this approach remains ineffective for most patients. Studies indicate that T cell exhaustion (Tex) is epigenetically encoded, and PD-1 blockade can only partially restore T cell activity. Chronic, non-resolving inflammation fosters an immunosuppressive tumor microenvironment (TME) that promotes T cell exhaustion and contributes to immunotherapy resistance. Our goal is to promote the resolution of inflammation through the administration of D-series resolvins (RvDs) to restore leukocyte antitumor activity and reverse immunosuppression and immunotherapy resistance within the TME.
We employed in vitro and in vivo models of HPV-positive head and neck cancer (HNC). Activated CD8+ T cells, isolated from human peripheral blood, were co-cultured with either tumor cell lines or primary tumor cells derived from patient biopsies. Cultures were stimulated with RvD5, a pro-resolving lipid mediator that promotes the resolution of inflammation. Syngeneic and NGS mouse models were treated with RvD5, anti-PD-1, and/or anti-CTLA-4 immunotherapies. Samples were analyzed by flow cytometry, cytokine profiling, lipidomics, bulk RNA sequencing, and single-cell RNA sequencing.
We found that RvD5 reduced PD-1 expression on T cells and PD-L1 expression on cancer cells, thereby restoring T cell antitumor functions by delaying their differentiation into Tex. In vivo, RvD5 inhibited tumor growth. Notably, when combined with anti-PD-1 therapy, RvD5 enhanced tumor response rates, suggesting that shifting cancer-associated inflammation toward resolution can improve ICI efficacy.
Thus, RvD5 suppresses tumor growth by dampening inflammation and delaying T cell exhaustion within the TME. By reshaping CD8+ T cell responses, RvDs may represent a promising therapeutic strategy to strengthen antitumor immunity and overcome resistance to immunotherapy.
AIRC (MFAG 2022 — ID. 27060)
Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
It is demonstrated that PD-1 inhibition enhances CD4+ T cell function, specifically through increased IL-21 production from T follicular helper (Tfh) cells which promotes both humoral and cytotoxic antiviral responses.
Prajakta Warang, J. Teijaro· Journal of Immunology· 0 citations
The immunosuppressive tumor microenvironment (TME), orchestrated largely by tumor -infiltrating regulatory T cells (TI -Tregs), represents a critical barrier to effective cancer immunotherapy. This review focuses on the chemokine receptor CCR8, which has recently emerged as a highly promising and specific target for therapeutic intervention due to its preferential and stable expression on highly suppressive TI -Treg subsets. We synthesize current evidence demonstrating that CCR8 is selectively upregulated on TI -Tregs across multiple solid tumor types, where its expression correlates with poor patient prognosis and resistance to immune checkpoint inhibitors (ICIs). This expression pattern —enriched within the tumor but minimal in peripheral blood and normal tissues —provides a compelling rationale for tumor -selective targeting. We critically examine the primary therapeutic strategies under development, including ADCC -enhanced monoclonal antibodies, which have shown the most clinical promise, alongside bispecific antibodies and small molecule antagonists. While early -phase clinical trials report encouraging safety and on -target pharmacodynamic activity, the field faces significant challenges. These include unresolved questions regarding CCR8's functional role versus its value as a targeting biomarker, a lack of validated predictive biomarkers for patient stratification, and the physical barriers to effective drug delivery in solid tumors. This review aims to provide a comprehensive and nuanced understanding of CCR8 biology and to outline the key steps necessary for the successful clinical translation of CCR8-targeted therapies.
Cytotoxic CD8 T cells play a crucial role in eliminating infections and cancer. However, chronic antigen exposure induces their development into exhausted T (TEX) cells. TEX cells exhibit increased inhibitory receptors or checkpoints expression, defective effector functions and thus unable to eliminate the virus-infected cells and cancers. Antibodies inhibiting signaling through checkpoints PD1 or CTLA4 (immune checkpoint blockade or ICB) induce differentiation of TEX cells into effectors that eliminate cancer and viral infected cells. PD1 blockade is the leading ICB against several tumor types. However, > 50% of the cancer patients either do not respond or get durable benefits from PD1 blockade. Therefore, there is an urgent need to understand the PD1-independent mechanism to improve immunotherapy against tumors resistant to PD1 blockade.
In order to address the role of UFL-1 in CD8 T cell exhaustion, we used LCMV acute and chronic infection models in control and CD4 specific UFL-1 knockout mice. Different subset of CD8 T cells and their differentiation status and functional response upon activation were analyzed using flow cytometry and ScRNA-seq.
Acute exposure to antigens, is not known to cause T cell exhaustion. We found that UFL1-deficient CD8 T cells undergo exhaustion during acute viral infection. During chronic antigen presence, such as in tumor models and chronic viral infections, UFL1 deficiency worsens CD8 T cell exhaustion. Additionally, the PD1 blockade fails to improve the functionality of UFL1-deficient TEX cells. Consistent with this, UFL1 expression in tumor-infiltrating CD8 T cells is positively correlated with the progression-free survival of melanoma patients treated with PD1 blockade.
These findings suggest that exhaustion in UFL1-deficient CD8 T cells is PD1-independent. Therefore, understanding how UFL1 prevents T cell exhaustion would help discover new ways to improve immunotherapies, especially for cancers that do not respond to PD1 blockade.
NIH Funding - NIAID00054
Immune Response Regulation: Molecular Mechanisms (IRM)
Aravind Rathakrishnan, Nagendra Singh, Francis Anazodo et al.· Journal of Immunology· 0 citations
Despite advancements in immunotherapy, more than half of melanoma patients will either not respond or will later relapse after treatment with immune checkpoint blockade (ICB). For later-stage patients, chemotherapy is an essential treatment modality, but tumor intrinsic cell survival mechanisms and an immunosuppressive tumor microenvironment often limit efficacy. We recently discovered that by upregulating the secretion of Pros1, tumor cells limit the response of macrophages to chemotherapy released tumor Damage Associated Molecular Patterns (DAMPs). By pharmacologically inhibiting Ptp1b, a signaling intermediary downstream of the Mer receptor, macrophage responsiveness to DAMPs can be restored. This is associated with increased macrophage M1 polarization and immune infiltration, as well as a 40-80% decrease in tumor volume in multiple preclinical models.
We hypothesize that because Ptp1b inhibition prevents tumor suppression of DAMP responsiveness, combining Ptp1b inhibition may improve the efficacy of multiple chemotherapies, particularly those that promote necrotic and immunogenic cell death. To test this, macrophages were co-cultured with murine melanoma cells (B16F10) and cisplatin, doxorubicin, or dacarbazine in the presence or absence of Ptp1b inhibitor via transwell assay, after determining the relative amounts of apoptosis/necrosis produced by each chemotherapy.
Preliminary results indicate that Ptp1b inhibition significantly increases macrophage pro-inflammatory gene expression by 7.5-fold in a setting of chemotherapy-induced tumor DAMP release. This indicates that inhibiting Ptp1b could synergistically improve chemotherapy effectiveness.
As Ptp1b inhibitors have a reasonable safety profile based on multiple clinical trials, combining Ptp1b inhibiting drugs with chemotherapy may be a novel way to restore the innate immune response during treatment while also improving patient outcomes.
NCI- RO1 CA262241(Ubil)
Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Oluwaseyi Omodiminiyi, Nestor Prieto-Dominguez, Eric Ubil· Journal of Immunology· 0 citations
Immune checkpoint blockade (ICB) has advanced the treatment of melanoma and other cancer types. Despite its success, only about half of the treated patients respond, with many developing resistances. One contributing factor is the poor infiltration of effector T cells in the solid tumors, along with the immunosuppression caused by regulatory T (Treg) cells. CCR7+ dendritic cells (DC) interact with T cells, by either supporting the survival of CD8 T cells or promoting the migration of Tregs. While they are known to play a role in mediating tumor immune responses, their specific functions in controlling tumors and T cell responses remain poorly understood.
We generated innovative mouse models such as the inducible CCR7+DC conditional knock out (cKO), to defined how CCR7+DC use CD83 to restrain CD8 T cell effector responses and promote tumor growth.
Reducing the expression of the activation maker CD83 on CCR7+DC, either directly or via blocking its soluble form expressed by Tregs, enhanced intratumoral CD8 T cell accumulation and controlled tumor growth in mice. Genetic perturbation of CD83 retains a pro-inflammatory IL-12+ CCR7+DC state, which is associated with the expansion of effector-like CD8 T cells and improved tumor control. Mechanistically, Tregs regulate IL-12 expression on CCR7+DC via STAT signaling in a CD83 dependent manner in vitro. Furthermore, we also show that CD83 levels on CCR7+DC negatively correlate with intratumoral CD8 T cell infiltration in several human cancers.
This study demonstrates that the ablation of interaction of CD83 molecule between CCR7+DC and Tregs results in increased anti-tumor immune response. Our findings identify CD83 as a cellular and molecular checkpoint that restrains T cell responses and can be targeted therapeutically.
This work was supported by funding for M.D.P from Cancer Prevention and Research Institute of Texas (CPRIT; RR210017) Robert J. Kleberg, Jr. and Helen C. Foundation Melanoma SPORE Developmental Research Program (DRP; P50CA221703) American Association of I
Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Ruparoshni Jayabalan, Ricardo Gonzalez-Delgado, Luis A. Castillo Montanez et al.· Journal of Immunology· 0 citations
A complementary therapeutic strategy is discussed: engineering T cells for greater durability in the TME through knockout of exhaustion-associated transcription factors, and reprogramming tumour cells with DNA methyltransferase (DNMTi) and histone deacetylase (HDACi) inhibitors to restore immunogenicity.
L. Saltis, Liew Jun Mun· Pathology, Research and Prac...· 0 citations
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