Re-education of the Tumor Microenvironment With Targeted Therapies and Immunotherapies

Abstract

The clinical success of cancer immunotherapies targeting PD-1 and CTLA-4 has ignited a substantial research effort to improve our understanding of tumor immunity. Recent studies have revealed that the immune contexture of a tumor influences therapeutic response and survival benefit for cancer patients. Identifying treatment modalities that limit immunosuppression, relieve T cell exhaustion, and potentiate effector functions in the tumor microenvironment (TME) is of much interest. In particular, combinatorial therapeutic approaches that re-educate the TME by limiting the accumulation of immunosuppressive immune cells, such as Foxp3 regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), while promoting CD8 + and CD4 + effector T cell activity is critical. Here, we review key approaches to target these immunosuppressive immune cell subsets and signaling molecules and define the impact of these changes to the tumor milieu. We will highlight the preclinical and clinical evidence for their ability to improve anti-tumor immune responses as well as strategies and challenges for their implementation. Together, this review will provide understanding of therapeutic approaches to efficiently shape the TME and reinvigorate the immune response against cancer.

Identification of a ceRNA Network in Lung Adenocarcinoma Based on Integration Analysis of Tumor-Associated Macrophage Signature Genes

“…However, TAMs are highly plastic and heterogeneous in solid tumor ( Ngiow and Young, 2020 ). Generally, Th1 cytokines such as lipopolysaccharide (LPS), interferon-γ (IFN-γ), and tumor necrosis factor-α induce macrophages into a M1-like phenotype, playing a role in antitumor inflammation.…”

PD-1-stimulated T cell subsets are transcriptionally and functionally distinct

“…However, it is also becoming increasingly clear that CD8 T cell-binding of neoantigens is insufficient for mounting a powerful antitumor response, and immunotherapy-induced antitumor responses require the added presence of CD4 T cells ( Kennedy and Celis, 2008 ). Multiple studies have indicated that CD4 T cells mediate antitumor effects through mechanisms that vary according to tumor microenvironments ( Ngiow and Young, 2020 ). In some settings, CD4 T cells became cytotoxic in the presence of IL-2, or in the absence of regulatory T cells ( Zuazo et al., 2020 ).…”

Exploring the Emerging Role of the Gut Microbiota and Tumor Microenvironment in Cancer Immunotherapy

“…The refining of molecular cells and immune regulation of therapeutic targets is increasing in the TME, and the clinical application also is growing more and more widely, for example, that resistance to PD-1/PD-L1 plays multiple roles in tumor immunotherapy, however, the test of limited activity PD-1 of resisting tumor types may have a good therapeutic effect in the strategy of reshaping the tumor inert environment in the future. Namely the possibility of immunotoxicity and immunotherapy to enhance antitumor immunity, in other words, use reasonable and selective combined immunotherapy in a limited TME to reactivate the anti-tumor immune response ( 185 ).…”