PD-L1, CD4+, and CD8+ Tumor-Infiltrating Lymphocytes (TILs) Expression Profiles in Melanoma Tumor Microenvironment Cells

Caraban, B.M.; Matei, Elena; Cozaru, Georgeta Camelia; Aşchie, Mariana; Deacu, Mariana; Enciu, Manuela; Bălțătescu, Gabriela Izabela; Chisoi, Anca; Dobrin, Nicolae; Petcu, Lucian Cristian; Gheorghe, Emma; Hangan, L.T.; Roșu, Mihai Cătălin; Orășanu, Cristian Ionuț; Nicolau, Antonela-Anca

doi:10.3390/jpm13020221

Cited by 12 publications

(6 citation statements)

References 80 publications

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“…However, it remains unclear as to which cell would be most suitable to determine a response to anti-PD-1 antibodies. 26 By the same token, presence of increased TILs could also point towards high PD-L1 expression, 27–29 as was seen in the present study ( P < .001).…”

Section: Discussionsupporting

confidence: 82%

PD-L1 Expression in Ampullary Adenocarcinoma

et al. 2023

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Introduction Ampullary adenocarcinoma is a rare neoplasm often treated by the complex Whipple's procedure. Several histological factors predict poor prognosis including pancreatobiliary morphology, presence of lymphovascular, perineural invasion and local or distant metastasis. Systemic therapy with gemcitabine, 5-fluorouracil regimens are given with variable benefits. Immunotherapy checkpoint inhibitors have shown beneficial anti-tumor effects in several carcinomas, the most remarkable being in non-small cell lung cancer. Administration of these novel drugs is based on immunohistochemical expression (which may or may not be indicative of response to therapy) along with meticulous decision making by the multidisciplinary team. Immunohistochemistry (IHC) is an effective means of immune marker demonstration and has been used in various tumor types for predictive and prognostic purposes. Methods PD-L1 IHC (clone E1L3N) was applied in 101 cases of ampullary adenocarcinoma. Tumor infiltrating lymphocytes were also evaluated. The immunoreactivity was assessed and categorized into following staining thresholds: <1%, <5%, <10% and ≥10% for tumor cells (membranous and/or cytoplasmic staining pattern), and 5% and 10% cut-offs for immune cells. Results We found that at a 10% cut-off, 73.3% (74/101) patients were men ( P = .006) older than 50 years of age ( P < .001) presenting with a tumor measuring <3 cm ( P = .001). It was significantly associated with intestinal differentiation ( P = .004) and grade 1 tumors ( P = .001). Twelve patients presented with recurrence as well ( P = .03). Conclusion In the context of ampullary adenocarcinoma, this study highlights the positivity observed with the PD-L1 IHC clone E1L3N at different thresholds, with the particularly stronger associations being evident at a 10% cut-off.

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Section: Discussionsupporting

confidence: 82%

PD-L1 Expression in Ampullary Adenocarcinoma

et al. 2023

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“…Thus, targeting the Wnt/β-catenin signaling pathway in immune cells (e.g., T lymphocyte, NK cells and macrophage) may restore the patient's immunocompetence. Historical studies have shown that melanoma is also one of the most immunomodulatory-sensitive malignancies, and intensive infiltration being correlated to favorable prognosis [ 49 , 50 ]. We speculate that there may be interactions between PDPN and tumor-infiltrating immune cells.…”

Section: Discussionmentioning

confidence: 99%

A novel PDPN antagonist peptide CY12-RP2 inhibits melanoma growth via Wnt/β-catenin and modulates the immune cells

Feng,

Yu,

Wang

et al. 2024

J Exp Clin Cancer Res

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Background Podoplanin (PDPN) is a highly conserved, mucin-type protein specific to the lymphatic system. Overexpression of PDPN is associated with the progression of various solid tumors, and plays an important roles in the tumor microenvironment by regulating the immune system. However, the role of PDPN-mediated signal activation in the progression of melanoma is still unknown. Methods PDPN expression was first analyzed in 112 human melanoma tissue microarrays and melanoma cell lines. Functional experiments including proliferation, clone formation, migration, and metastasis were utilized to identify the suppressive effects of PDPN. The Ph.D.TM-12 Phage Display Peptide Library was used to obtain a PDPN antagonist peptide, named CY12-RP2. The immunofluorescence, SPR assay, and flow cytometry were used to identify the binding specificity of CY12-RP2 with PDPN in melanoma cells. Functional and mechanistic assays in vivo and in vitro were performed for discriminating the antitumor and immune activation effects of CY12-RP2. Results PDPN was overexpressed in melanoma tissue and cells, and inhibited melanoma cells proliferation, migration, and metastasis by blocking the EMT and Wnt/β-catenin pathway. PDPN antagonistic peptide, CY12-RP2, could specifically bind with PDPN, suppressing melanoma various functions inducing apoptosis in both melanoma cells and 3D spheroids. CY12-RP2 also enhanced the anti-tumor capacity of PBMC, and inhibited melanoma cells growth both in xenografts and allogeneic mice model. Moreover, CY12-RP2 could inhibit melanoma lung metastasis, and abrogated the immunosuppressive effects of PDPN by increasing the proportion of CD3 + CD4 + T cells, CD3 + CD8 + T cells, CD49b + Granzyme B + NK cells, and CD11b + CD86 + M1-like macrophages and the levels of IL-1β, TNF-α, and IFN-γ. Conclusions This study has demonstrated the important role of PDPN in the progression of melanoma and formation of immunosuppressive environment, and provided a potential approach of treating melanoma using the novel CY12-RP2 peptide. Graphical Abstract In melanoma, PDPN is overexpressed in the cancer cells, and promotes melanoma cells growth and metastasis through activating the Wnt/β-catenin pathway. Treatment with the PDPN antagonistic peptide CY12-RP2 could not only inhibit the melanoma growth and metastasis both in vitro and in vivo through Wnt/β-catenin pathway blockade, but also abrogate the immunosuppressive effects of PDPN through modulating immune cells.

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“…1 We were particularly drawn to the PD-1/PD-L1 cascade with the well characterized relationship between increased PD-1 expression and suppressed T cell function along with the observation that tumor cells and regulatory/support cells both can express PD-L1 to evade T-cell-mediated antitumor immunity. The presence of PD-L1 is a negative prognostic marker 17,18 with reports of circulating PD-L1 positive monocytes, associated with some cancers. [19][20][21] Hence, we hypothesized that designing PD-L1 targeting CAR T-cells would not only be able to strike tumor cells but would also attack the PD-L1 expressing regulatory/support cells resulting in the destabilization of the cellular network that generates the immunosuppressive TME.…”

Section: Gbm Patient-derived Mc9999 Car T-cells Targeted Primary Gbm ...mentioning

confidence: 99%

Advancing CAR T-Cell Therapy: Simultaneously Attack Tumor and Immunosuppressive Cells in the Tumor Microenvironment

Luo,

Garavito,

Brooks

et al. 2024

Preprint

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Chimeric antigen receptor (CAR) T-cell therapy has encountered limited success in solid tumors. The lack of dependable antigens and the immunosuppressive tumor microenvironment (TME) are major challenges. Within the TME, tumor cells along with immunosuppressive cells employ an immune-evasion mechanism that upregulates programmed death ligand 1 (PD-L1) to deactivate effector T cells; this makes PD-L1 a reliable, universal target for solid tumors. We developed a novel PD-L1 CAR (MC9999) using our humanized anti-PD-L1 monoclonal antibody, designed to simultaneously target tumor and immunosuppressive cells. The antigen-specific antitumor effects of MC9999 CAR T-cells were observed consistently across four solid tumor models: breast cancer, lung cancer, melanoma, and glioblastoma multiforme (GBM). Notably, intravenous administration of MC9999 CAR T-cells eradicated intracranially established LN229 GBM tumors, suggesting penetration of the blood-brain barrier. The proof-of-concept data demonstrate the cytolytic effect of MC9999 CAR T-cells against immunosuppressive cells, including microglia HMC3 cells and M2 macrophages. Furthermore, MC9999 CAR T-cells elicited cytotoxicity against primary tumor-associated macrophages within GBM tumors. The concept of targeting both tumor and immunosuppressive cells with MC9999 was further validated using CAR T-cells derived from cancer patients. These findings establish MC9999 as a foundation for the development of effective CAR T-cell therapies against solid tumors.

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PD-L1, CD4+, and CD8+ Tumor-Infiltrating Lymphocytes (TILs) Expression Profiles in Melanoma Tumor Microenvironment Cells

Cited by 12 publications

References 80 publications

PD-L1 Expression in Ampullary Adenocarcinoma

PD-L1 Expression in Ampullary Adenocarcinoma

A novel PDPN antagonist peptide CY12-RP2 inhibits melanoma growth via Wnt/β-catenin and modulates the immune cells

Advancing CAR T-Cell Therapy: Simultaneously Attack Tumor and Immunosuppressive Cells in the Tumor Microenvironment

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