Anti-tumor Immunity In Tumor Microenvironment Research Articles

Research progress on the role of PTEN deletion or mutation in the immune microenvironment of glioblastoma.

Recent advances in immunotherapy represent a breakthrough in solid tumor treatment but the existing data indicate that immunotherapy is not effective in improving the survival time of patients with glioblastoma. The tumor microenvironment (TME) exerts a series of inhibitory effects on immune effector cells, which limits the clinical application of immunotherapy. Growing evidence shows that phosphate and tension homology deleted on chromosome ten (PTEN) plays an essential role in TME immunosuppression of glioblastoma. Emerging evidence also indicates that targeting PTEN can improve the anti-tumor immunity in TME and enhance the immunotherapy effect, highlighting the potential of PTEN as a promising therapeutic target. This review summarizes the function and specific upstream and downstream targets of PTEN-associated immune cells in glioblastoma TME, providing potential drug targets and therapeutic options for glioblastoma.

Abstract 5307: Preclinical evaluation of a potential FIC 4-1BB/CD24 bispecific antibody IBD0333

Abstract Background: This study demonstrates the preclinical evaluation of a novel 4-1BB/CD24 bispecific antibody IBD0333. 4-1BB’s activation triggers a signaling cascade that activates both innate and adaptive immune systems. Due to the hepatotoxicity of current anti-4-1BB monoclonal antibodies, tumor-associated antigens (TAA) targeting to specifically activate immune cells in the tumor microenvironment (TME) is expected to enhance its safety profile. CD24 is highly expressed in many cancers, such as ovarian and breast cancer and its high expression is often related to poor prognosis. The signaling pathway of CD24/Siglec-10 triggers a “don’t eat me” signal that facilitates immune escape of tumor cells. Therefore, IBD0333 was designed to target CD24 overexpressed tumor cells and activate CD8+ T cells to induce T cell mediated antitumor immunity in TME of the targeted tumor tissue. To further reduce the toxicity risk, the anti-4-1BB moiety is designed to activate the signaling pathway only when IBD0333 binds to the tumor cells that overexpress CD24. Methods: For CD24 terminus, we applied virus like particle (VLP) as antigen for immunization to obtain functional CD24 antibodies. For 4-1BB terminus, competitive ELISA/FACS analysis as well as amino acid point mutation binding ability analysis based on the receptor crystal structure were performed to characterize the binding epitope. The in vivo mice efficacy and toxicity study, as well as cynomolgus monkey toxicity study were also conducted to describe the anti-tumor activity and safety profile. For IBD0333, we verified binding affinity by FACS to cancer cells and the 4-1BB activity in reporter-gene assay. IL2 and INF-γ secretion assay were performed to evaluate the PBMC activation. C57BL/6J-h4-1BB humanized mice bearing MC38-hCD24 colon cancer cells were used to validate the anti-tumor efficacy of IBD0333. Preclinical PK and toxicity study was also performed in cynomolgus monkeys to describe the safety profile of IBD0333. Results: IBD0333 showed excellent binding and PBMC stimulation activities. In toxicology studies of IBD0333, no obvious abnormality in mice or cynomolgus monkeys administered with IBD0333 was observed. The MTD was estimated to be greater than 200 mg/kg with no severe side effects observed in the study, showing that IBD0333 has great potential to achieve significantly improved safety profile. As to efficacy, IBD0333 showed excellent tumor inhibition activities in mice model with 99% tumor growth inhibition at 1 mg/kg and 100% at 3 mg/kg. Conclusion: IBD0333 is a clinical stage, potential first-in-class, 4-1BB/CD24 bsAb that simultaneously stimulates both innate and adaptive immunity to achieve strong synergistic effects with reduced hepatotoxicity. The IND approvals from the FDA and the NMPA have been obtained and the Phase I clinical trial of IBD0333 in locally advanced/metastatic solid tumors or non-Hodgkin’s lymphoma is currently on-going. Citation Format: Xiaoling Jiang, Chongbing Wu, Zi Chen, Liusong Yin. Preclinical evaluation of a potential FIC 4-1BB/CD24 bispecific antibody IBD0333 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5307.

Conserved angio-immune subtypes of the tumor microenvironment predict response to immune checkpoint blockade therapy

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment. However, only a fraction of patients respond to ICB therapy. Accurate prediction of patients to likely respond to ICB would maximize the efficacy of ICB therapy. The tumor microenvironment (TME) dictates tumor progression and therapy outcome. Here, we classify the TME by analyzing the transcriptome from 11,069 cancer patients based on angiogenesis and Tcell activity. We find three distinct angio-immune TME subtypes conserved across 30 non-hematological cancers. There is a clear inverse relationship between angiogenesis and anti-tumor immunity in TME. Remarkably, patients displaying TME with low angiogenesis with strong anti-tumor immunity show the most significant responses to ICB therapy in four cancer types. Re-evaluation of the renal cell carcinoma clinical trials provides compelling evidence that the baseline angio-immune state is robustly predictive of ICB responses. This study offers a rationale for incorporating baseline angio-immune scores for future ICB treatment strategies.

ZL-1211 Exhibits Robust Antitumor Activity by Enhancing ADCC and Activating NK Cell-mediated Inflammation in CLDN18.2-High and -Low Expressing Gastric Cancer Models.

ZL-1211, anti-CLDN18.2 therapeutic antibody can target CLDN18.2-high as well as -low gastric cancers that may not be eligible for treatment with clinical benchmark. ZL-1211 treatment induces NK-cell activation with robust inflammation to further activate antitumor immunity in tumor microenvironment.

Inhibitory functions of PD-L1 and PD-L2 in the regulation of anti-tumor immunity in murine tumor microenvironment.

Although a role of PD-L1 in the suppression of anti-tumor immunity and its value as a predictive biomarker has been suggested by various preclinical and clinical studies, theprecise mechanisms how PD-L1 and PD-L2, another ligand of PD-1, regulate anti-tumor immunity in the tumor microenvironment are yet to be fully explored. Here, we address this issue using PD-L1-deficient tumor cells, PD-L1-knockout (KO) mice, anti-PD-L1 monoclonal antibody (mAb), and anti-PD-L2 mAb. Firstly, PD-L1-deficient or competent tumor cells were inoculated into wild-type or PD-L1-KO mice. Results of tumor growth and mouse survival indicated that both tumor- and host-derived PD-L1 are functional to suppress anti-tumor immunity, while the former contributes predominantly than the latter. Experiments using bone marrow (BM) chimeric mice, generated by transferring PD-L1-KO BM cells into wild-type mice or vice versa, further suggested that PD-L1 expressed on BM-derived hematopoietic cells mediates the suppressive effects on anti-tumor immunity. Secondly, anti-PD-L2 mAb treatment demonstrated a profound synergy with anti-PD-L1 mAb therapy, whereas anti-PD-L2 mAb alone hardly induced any anti-tumor effects, suggesting that PD-L2's function becomes evident when the effects of PD-L1 are abrogated by anti-PD-L1 mAb. Consistent with this notion, PD-L2 expression was upregulated on tumor-associated macrophages (TAM) when mice were treated with anti-PD-L1 mAb. Taken together, our study elucidated the importance of PD-L1 associated with tumor cells and non-tumor host cells, particularly BM-derived hematopoietic cells, as well as PD-L2 inducibly expressed on TAM in the suppression of anti-tumor immunity in the tumor microenvironment.