The Janus Face of Tumor Microenvironment Targeted by Immunotherapy

Abstract

The tumor microenvironment (TME) is a complex entity where host immune and non-immune cells establish a dynamic crosstalk with cancer cells. Through cell-cell interactions, which are mediated by key signals, such as the PD-1/PD-L1 axis, as well as the release of soluble mediators, this articulated process defines the nature of TME determining tumor development, prognosis, and response to therapy. Specifically, tumors are characterized by cellular plasticity that allows for the microenvironment to polarize towards inflammation or immunosuppression. Thus, the dynamic crosstalk among cancer, stromal, and immune components crucially favors the dominance of one of the Janus-faced contexture of TME crucial to the outcome of tumor development and therapeutic response. However, mostly, TME is dominated by an immunosuppressive landscape that blocks antitumor immunity and sustain tumor progression. Hence, in most cases, the immunosuppressive components of TME are highly competent in suppressing tumor-specific CD8+ T lymphocytes, the effectors of cancer destruction. In this complex context, immunotherapy aims to arm the hidden Janus face of TME disclosing and potentiating antitumor immune signals. Herein, we discuss recent knowledge on the immunosuppressive crosstalk within TME, and share perspectives on how immunotherapeutic approaches may exploit tumor immune signals to generate antitumor immunity.

The Use of Alternative Strategies for Enhanced Nanoparticle Delivery to Solid Tumors

“… 146 In combination with the lack of immune activation in the TME, the downregulation of NK cells and adhesion molecules ICAM-1 and VCAM-1 as well as CD62L on the surface of CD8+ T cells hinders effective antitumor immune response. 147 , 148 …”

CRISPR/Cas: From Tumor Gene Editing to T Cell-Based Immunotherapy of Cancer

“…Among all the immune system members present at TME, macrophages and T cells are the most distorted. Tumor-associated macrophages (TAMs) support tumorigenesis and metastasis and inhibit antitumor responses by releasing EGF, IL-6, TNF, MMPs, VEGFA, TGF-β, IL-10, and PD-L1 ( 98 , 99 ). In addition, T cells’ anti-tumor activity and metabolic state is disrupted by the immune-modulatory cytokines present in the TME and the immune checkpoint inhibitors such as PD-1 and CTLA-4 ( 99 , 100 ).…”

“…Tumor-associated macrophages (TAMs) support tumorigenesis and metastasis and inhibit antitumor responses by releasing EGF, IL-6, TNF, MMPs, VEGFA, TGF-β, IL-10, and PD-L1 ( 98 , 99 ). In addition, T cells’ anti-tumor activity and metabolic state is disrupted by the immune-modulatory cytokines present in the TME and the immune checkpoint inhibitors such as PD-1 and CTLA-4 ( 99 , 100 ). Accordingly, a study by Chung et al on 11 breast cancer cases revealed that the presence of M2 macrophages in the TME was correlated with T cell exhaustion ( 101 ).…”

Overcoming Biological Barriers With Block Copolymers-Based Self-Assembled Nanocarriers. Recent Advances in Delivery of Anticancer Therapeutics

“…Tumor cells also downregulate NK cells to prevent exposure of tumor necrosis factor-related apoptosis inducing ligand (Waldhauer and Steinle, 2008). Due to decrease trafficking in tumor sites (including downregulation of cluster of differentiation (CD) 62L on CD8 + T cells, the adhesion molecules VCAM-1 and ICAM-1, and IL-12) and lack of activation caused by the aforementioned immunosuppressive tumor microenvironment, the CD8 + T cells are not able to exhibit an inhibitory response against tumors (Buoncervello et al, 2019). Thus, targeting immune cells or immune related specific molecules could reshape the immune microenvironment and increase the treatment efficacy.…”