Distinct immune microenvironment profiles of therapeutic responders emerge in combined TGFβ/PD-L1 blockade-treated squamous cell carcinoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Strait AA
PROVIDER: S-EPMC8387430 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:IntroductionIn solid tumor immunotherapy, less than 20% of patients respond to anti-programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) agents. The role of transforming growth factor β (TGFβ) in diverse immunity is well-established; however, systemic blockade of TGFβ is associated with toxicity. Accumulating evidence suggests the role of crosstalk between TGFβ and PD-1/PD-L1 pathways.Areas coveredWe focus on TGFβ and PD-1/PD-L1 signaling pathway crosstalk and the determinant role of TGFβ in the resistance of immune checkpoint blockade. We provide the rationale for combination anti-TGFβ and anti-PD-1/PD-L1 therapies for solid tumors and discuss the current status of dual blockade therapy in preclinical and clinical studies.Expert opinionThe heterogeneity of tumor microenvironment across solid tumors complicates patient selection, treatment regimens, and response and toxicity assessment for investigation of dual blockade agents. However, clinical knowledge from single-agent studies provides infrastructure to translate dual blockade therapies. Dual TGFβ and PD-1/PD-L1 blockade results in enhanced T-cell infiltration into tumors, a primary requisite for successful immunotherapy. A bifunctional fusion protein specifically targets TGFβ in the tumor microenvironment, avoiding systemic toxicity, and prevents interaction of PD-1+ cytotoxic cells with PD-L1+ tumor cells.
| S-EPMC10085570 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) is a powerful oncologic treatment modality for a wide variety of human malignancies, but the patient response rate to this treatment remains low, especially in patients with cutaneous squamous cell carcinoma (cSCC). 5-Aminoleuvulinic acid-photodynamic therapy (ALA-PDT) is widely used to treat cancerous and precancerous skin diseases, but the value of ALA-PDT in the treatment of invasive cSCC is debatable. Our previous studies have shown that ALA-PDT can induce antitumor immune responses by promoting the immunogenic death of tumor cells. However, it is unclear whether ALA-PDT exerts synergistic effects with ICB in cSCC. Here, we report that PD-L1 blockade potentiates the antitumor effects of ALA-PDT both on primary and distant tumors, and optimizes the tumor microenvironment in cSCC. In this study, we first detected PD-L1 expression in patients with different grades of cSCC. Then we found the combination of anti-PD-L1 monoclonal antibody (mAb) and ALA-PDT killed tumor cells by apoptosis- and/or ferroptosis-mediated immunogenic cell death (ICD) and stimulated systemic immune response, as well as building the immunological memory response to prevent tumor recurrence. Furthermore, we found that combination therapy can be used to recruit tertiary lymphoid structure (TLS)-like intratumoral lymphoid aggregates, which may promote tumor-infiltrating lymphocyte (TIL)-mediated antitumor immunity. In summary, our work demonstrates that ICB treatment with an anti-PD-L1 antibody is a promising strategy that may potentiate the antitumor effects of ALA-PDT in cSCC.
| S-EPMC8986186 | biostudies-literature
Project description:Immune checkpoint inhibitors targeting the interaction between programmed cell death-1 (PD-1) and its ligand PD-L1 induce tumor regression in a subset of non-small cell lung cancer patients. However, clinical response rates are less than 25%. Evaluation of combinations of immunotherapy with existing therapies requires appropriate preclinical animal models. In this study, murine lung cancer cells (CMT167 and LLC) were implanted either orthotopically in the lung or subcutaneously in syngeneic mice, and response to anti-PD-1/PD-L1 therapy was determined. Anti-PD-1/PD-L1 therapy inhibited CMT167 orthotopic lung tumors by 95%. The same treatments inhibited CMT167 subcutaneous tumors by only 30% and LLC orthotopic lung tumors by 35%. CMT167 subcutaneous tumors had more Foxp3+ CD4+ T cells and fewer PD-1+ CD4+ T cells compared with CMT167 orthotopic tumors. Flow cytometric analysis also demonstrated increased abundance of PD-L1high cells in the tumor microenvironment in CMT167 tumor-bearing lungs compared with CMT167 subcutaneous tumors or LLC tumor-bearing lungs. Silencing PD-L1 expression in CMT167 cells resulted in smaller orthotopic tumors that remained sensitive to anti-PD-L1 therapy, whereas implantation of CMT167 cells into PD-L1- mice blocked orthotopic tumor growth, indicating a role for PD-L1 in both the cancer cell and the microenvironment. These findings indicate that the response of cancer cells to immunotherapy will be determined by both intrinsic properties of the cancer cells and specific interactions with the microenvironment. Experimental models that accurately recapitulate the lung tumor microenvironment are useful for evaluation of immunotherapeutic agents. Cancer Immunol Res; 5(9); 767-77. ©2017 AACR.
| S-EPMC5787226 | biostudies-literature
Project description:Immune checkpoint blockade therapies fail to induce responses in the majority of cancer patients, so how to increase the objective response rate becomes an urgent challenge. Here, we demonstrate that sufficient T cell infiltration in tumor tissues is a prerequisite for response to PD-L1 blockade. Targeting tumors with tumor necrosis factor superfamily member LIGHT activates lymphotoxin β-receptor signaling, leading to the production of chemokines that recruit massive numbers of T cells. Furthermore, targeting non-T cell-inflamed tumor tissues by antibody-guided LIGHT creates a T cell-inflamed microenvironment and overcomes tumor resistance to checkpoint blockade. Our data indicate that targeting LIGHT might be a potent strategy to increase the responses to checkpoint blockades and other immunotherapies in non-T cell-inflamed tumors.
| S-EPMC4794755 | biostudies-literature
Project description:BackgroundDespite the considerable advancement in the field of medicine over recent decades, laryngeal cancer continues to be a challenge. The field of immune oncology has generated promising immunomodulation therapies and opened up new ways of treatment.MethodsOur retrospective study included 102 patients diagnosed with laryngeal squamous cell cancer (LSCC). Immunohistochemistry was used to evaluate the expression of PD-L1 and tumor microenvironment cells (CD4, CD8, CD68 and CD163).ResultsPD-L1 expression showed statistically significant positive correlations with all examined tumor microenvironment cells. Patients with high CD68 and CD163 expression intratumorally (p = 0.0005 and p = 0.006, respectively) had statistically significant shorter disease-specific survival. Moreover, a statistically shorter time to recurrence was found in patients with high CD68 intratumoral and CD8 overall counts (p = 0.049 and p = 0.019, respectively). Also, high CD8 overall (>23%) and CD68 intratumoral (>2.7%) expression were statistically significant predictors of recurrence (p = 0.028, OR = 3.11 and p = 0.019, OR = 3.13, respectively).ConclusionsHigher CD68 and CD163 expression represented significantly worse prognosticators for clinical outcomes in patients with LSCC. In order to determine which LSCC patients will benefit from anti-PD-1/PD-L1 inhibitors, it is crucial to elucidate the relationship between PD-L1 expression, immune cell distribution and prognosis in LSCC patients.
| S-EPMC11311265 | biostudies-literature
Project description:Focal tumor cell PD-L1 expression adjacent to TIL can be used as a surrogate marker of an ongoing antitumor host response, which may be unleashed by PD-1 blockade. Tumor cell PD-L1 expression is superior to TIL PD-1 expression and the presence of TIL alone, when predicting response to anti-PD-1 therapy.
| S-EPMC4292419 | biostudies-other
Project description:Blockade of the pathway including programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers. Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma. However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood. We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted. Secretion of sPD-L1 resulted from alternate splicing activities, cytokine induction, cell stress, cell injury, and cell death in melanoma cells. Pretreatment levels of sPD-L1 were elevated in stage IV melanoma patient sera compared with healthy donors. High pretreatment levels of sPD-L1 were associated with increased likelihood of progressive disease in patients treated by CTLA-4 or PD-1 blockade. Although changes in circulating sPD-L1 early after treatment could not distinguish responders from those with progressive disease, after five months of treatment by CTLA-4 or PD-1 blockade patients who had increased circulating sPD-L1 had greater likelihood of developing a partial response. Induction of sPD-L1 was associated with increased circulating cytokines after CTLA-4 blockade but not following PD-1 blockade. Circulating sPD-L1 is a prognostic biomarker that may predict outcomes for subgroups of patients receiving checkpoint inhibitors. Cancer Immunol Res; 5(6); 480-92. ©2017 AACR.
| S-EPMC5642913 | biostudies-literature
Project description:Checkpoint inhibitors have been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients demonstrate a durable clinical response. PD-L1 scoring is currently the only biomarker measure routinely used to select patients for immunotherapy, but its predictive accuracy is modest. The aim of our study was to evaluate a proteomic assay for the analysis of patient plasma in the context of immunotherapy. Pretreatment plasma samples from 43 NSCLC patients who received anti-PD-(L)1 therapy were analyzed using a proximity extension assay (PEA) to quantify 92 different immune oncology-related proteins. The plasma protein levels were associated with clinical and histopathological parameters, as well as therapy response and survival. Unsupervised hierarchical cluster analysis revealed two patient groups with distinct protein profiles associated with high and low immune protein levels, designated as "hot" and "cold". Further supervised cluster analysis based on T-cell activation markers showed that higher levels of T-cell activation markers were associated with longer progression-free survival (PFS) (p < 0.01). The analysis of single proteins revealed that high plasma levels of CXCL9 and CXCL10 and low ADA levels were associated with better response and prolonged PFS (p < 0.05). Moreover, in an explorative response prediction model, the combination of protein markers (CXCL9, CXCL10, IL-15, CASP8, and ADA) resulted in higher accuracy in predicting response than tumor PD-L1 expression or each protein assayed individually. Our findings demonstrate a proof of concept for the use of multiplex plasma protein levels as a tool for anti-PD-(L)1 response prediction in NSCLC. Additionally, we identified protein signatures that could predict the response to anti-PD-(L)1 therapy.
| S-EPMC8268315 | biostudies-literature
Project description:BackgroundAlthough programmed cell death protein 1 (PD-1)/ programmed cell death-ligand protein 1 (PD-L1) checkpoint blockade immunotherapy demonstrates great promise in cancer treatment, poor infiltration of T cells resulted from tumor immunosuppressive microenvironment (TIME) and insufficient accumulation of anti-PD-L1 (αPD-L1) in tumor sites diminish the immune response. Herein, we reported a drug-loaded microbubble delivery system to overcome these obstacles and enhance PD-L1 blockade immunotherapy.MethodsDocetaxel (DTX) and imiquimod (R837)-loaded microbubbles (RD@MBs) were synthesized via a typical rotary evaporation method combined with mechanical oscillation. The targeted release of drugs was achieved by using the directional "bursting" capability of ultrasound-targeted microbubble destruction (UTMD) technology. The antitumor immune response by RD@MBs combining αPD-L1 were evaluated on 4T1 and CT26 tumor models.ResultsThe dying tumor cells induced by DTX release tumor-associated antigens (TAAs), together with R837, promoted the activation, proliferation and recruitment of T cells. Besides, UTMD technology and DTX enhanced the accumulation of αPD-L1 in tumor sites. Moreover, RD@MBs remolded TIME, including the polarization of M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, and reduction of myeloid-derived suppressor cells (MDSCs). The RD@MBs + αPD-L1 synergistic therapy not only effectively inhibited the growth of primary tumors, but also significantly inhibited the mimic distant tumors as well as lung metastases.ConclusionPD-L1 blockade immunotherapy was enhanced by RD@MBs delivery system.
| S-EPMC9909878 | biostudies-literature
Project description:The interaction between programmed cell death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) induces exhaustions of cytotoxic lymphocytes in the tumor microenvironment, which facilitates tumor immune evasion. PD-1/PD-L1 blockade therapy, which prevents the receptors and ligands from binding to each other, disrupts the T-cell exhaustion signaling, thereby increasing antitumor immunity. Inspiringly, it has revolutionized the treatment of many different types of cancers including non-small-cell lung carcinoma, melanoma, lymphoma, and so on. However, with the intention of generating an antitumor immune response, PD-1/PD-L1 blockade may also lead to a spectrum of side effects. The profile of adverse events (AEs) of PD-1/PD-L1 blockade is not exactly the same with other immune checkpoint blockades, such as blockade of cytotoxic T-lymphocyte-associated protein 4. Although cutaneous, gastrointestinal, and pulmonary systems are common victims, AEs of PD-1/PD-L1 blockade might occur in any other organ system of the human body. These toxicities can be life-threatening if not managed promptly, and proper treatment intervention is imperative for optimal control and prevention of severe damage. Currently, clinical practice for the management of AEs in PD-1/PD-L1 blockade remains sporadic and variable. The majority of initial clinical trials were carried out in Caucasians. The trials of multiple races usually included a small portion of Asian participants, and results were calculated and interpreted for the entire included subjects without any race-specific conclusions. Therefore, the information on PD-1/PD-L1 blockade in Asians is far from systematic or comprehensive. Recently, as the results of clinical trials of anti-PD-1/PD-L1 agents in Asian populations have been gradually released, we summarized current evidence with a specific focus on the Asian population, hoping to outline strategies and offer guidance on the management of AEs in cancer patients treated with PD-1/PD-L1 blockade in the Asian world.
| S-EPMC6614522 | biostudies-literature