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Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE225164 | GEO | 2023/02/18

REPOSITORIES: GEO

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Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [CD8 T]

Project description:Immune checkpoint inhibitors (ICIs) represented by anti-PD-1/PD-L1 antibodies have been widely applied for various cancers and the response rate to ICIs is closely associated with the tumor immune microenvironment (TIME). Here, we show that combinational targeting CCL7 and Fms-like tyrosine kinase 3 ligand (Flt3L) increases the infiltration and expansion of conventional type 1 dendritic cells (cDC1s) in tumor sites and enhances the T cell antitumor responses and the efficacy of anti-PD-1 therapy in subcutaneous tumor models and spontaneous KrasG12D non-small cell lung cancer (NSCLC) models. We demonstrate that the fusion protein PD-1Ab7 in which CCL7 is fused with the single chain fragment variable region of anti-PD-1 antibody (PD-1Ab) exhibits superior antitumor activities compared to PD-1Ab. Mechanistically, PD-1Ab7 promotes antitumor immunity by increasing the infiltration of cDC1s and the activation of T cells, which is severely compromised by depletion of Zbtb46+ cDCs or inhibition of the CCL7 receptor CCR2. Furthermore, complementation of Flt3L sensitizes the ICI-resistant tumors to PD-1Ab7 and synergizes with PD-1Ab7 to inhibit tumor progression. These findings highlight the essential roles of PD-1Ab-based chemokine fusion strategy in targeting cDC1s and T cells for cancer prevention and provide therapeutic lead molecules for antitumor immunotherapy.

2023-02-18 | GSE225163 | GEO

Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [Dendritic Cell]

2023-02-18 | GSE225126 | GEO

Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy

Project description:Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy

| PRJNA934274 | ENA

Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [CD8 T]

Project description:Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [CD8 T]

| PRJNA934477 | ENA

Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [Dendritic Cell]

Project description:Combinational targeting CCL7 and Flt3L to promote the expansion and infiltration of cDC1 in tumors enhances T cell activation and anti-PD-1 therapy [Dendritic Cell]

| PRJNA934064 | ENA

CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer.

Project description:The efficacy of checkpoint immunotherapy to non-small cell lung cancer (NSCLC) largely depends on the tumor microenvironment (TME). Here, we demonstrate that CCL7 facilitates anti-PD-1 therapy for the KrasLSL-G12D/+Tp53fl/fl (KP) and the KrasLSL-G12D/+Lkb1fl/fl (KL) NSCLC mouse models by recruiting conventional DC 1 (cDC1) into the TME to promote T cell expansion. CCL7 exhibits high expression in NSCLC tumor tissues and is positively correlated with the infiltration of cDC1 in the TME and the overall survival of NSCLC patients. CCL7 deficiency impairs the infiltration of cDC1 in the TME and the subsequent expansion of CD8+ and CD4+ T cells in bronchial draining lymph nodes and TME, thereby promoting tumor development in the KP mouse model. Administration of CCL7 into lungs alone or in combination with anti-PD-1 significantly inhibits tumor development and prolongs the survival of KP and KL mice. These findings suggest that CCL7 potentially serves as a biomarker and adjuvant for checkpoint immunotherapy of NSCLC.

| S-EPMC7704643 | biostudies-literature

PD-1/PD-L1 Based Combinational Cancer Therapy: Icing on the Cake.

Project description:Cancer has been a major global health problem due to its high morbidity and mortality. While many chemotherapy agents have been studied and applied in clinical trials or in clinic, their application is limited due to its toxic side effects and poor tolerability. Monoclonal antibodies specific to the PD-1 and PD-L1 immune checkpoints have been approved for the treatment of various tumors. However, the application of PD-1/PD-L1 inhibitors remains suboptimal and thus another strategy comes in to our sight involving the combination of checkpoint inhibitors with other agents, enhancing the therapeutic efficacy. Various novel promising approaches are now in clinical trials, just as icing on the cake. This review summarizes relevant investigations on combinatorial therapeutics based on PD-1/PD-L1 inhibition.

| S-EPMC7247431 | biostudies-literature

Flt3L therapy induces a Treg‐promoting cDC1 state in triple‐negative breast cancer

Project description:Conventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti‐tumor immune response. Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of Flt3L on the phenotype of distinct cDC subsets in the tumor microenvironment is still largely undetermined. Here, using multi‐omic single‐cell analysis, we show that Flt3L therapy increases all cDC subsets in orthotopic E0771 triple‐negative breast cancer, but this did not result in a reduction of tumor growth. Interestingly, a CD81+migcDC1 population, likely developing from cDC1, was induced upon Flt3L treatment. This subset is characterized by the expression of both canonical cDC1 markers as well as migratory cDC activation and regulatory markers and displayed a higher Treg‐inducing potential compared to other migcDCs. To shift the cDC phenotype towards a T‐cell stimulatory phenotype, CD40 agonist therapy was administered in combination with Flt3L. However, while αCD40 reduced tumor growth, Flt3L failed to improve the therapeutic response to αCD40 therapy. Interestingly, Flt3L+αCD40 combination therapy increased the abundance of Treg promoting CD81+migcDC1. Nonetheless, while Treg‐depletion and αCD40 therapy were synergistic, the addition of Flt3L to this combination did not result in any added benefit. Overall, these results indicate that merely increasing cDCs in the tumor by Flt3L treatment cannot improve anti‐tumor responses and therefore might not be beneficial for the treatment of triple‐negative breast cancer, though could still be of use to increase cDC numbers for autologous DC‐therapy.

2023-07-26 | GSE225539 | GEO

PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors.

Project description:Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a granulocyte macrophage colony-stimulating factor secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor-bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared with PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8 T lymphocytes and tumor-specific interferon-? production of CD8 T cells in the tumor microenvironment. Immunosuppressive pathways, including regulatory T cells and CTLA-4 expression on T cells were overcome by the addition of vaccine and low-dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment.

| S-EPMC4258151 | biostudies-other

Inducing Hypermutability to Promote Anti-PD-1 Therapy Response.

Project description:SummaryThe lack of clinical activity from various immune-checkpoint blockade approaches in mismatch repair- proficient (MMRp) colorectal cancer has demonstrated a critical need for novel approaches. In this issue, Crisafulli and colleagues provide proof of concept for the induction of hypermutability through the use of temozolomide as a potential pathway for enabling a productive anti-PD-1 immune response in MMRp colorectal cancer. See related article by Crisafulli et al., p. 1656 (1) .

| S-EPMC10373529 | biostudies-literature

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