Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment.

Nagaja Capitani,Laura Patrussi,Cosima T Baldari

doi:10.3390/ijms222011221

Nagaja Capitani, Laura Patrussi + Show 1 more

Open Access

https://doi.org/10.3390/ijms222011221

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Abstract

Similar to Janus, the two-faced god of Roman mythology, the tumor microenvironment operates two opposing and often conflicting activities, on the one hand fighting against tumor cells, while on the other hand, favoring their proliferation, survival and migration to other sites to establish metastases. In the tumor microenvironment, cytotoxic T cells—the specialized tumor-cell killers—also show this dual nature, operating their tumor-cell directed killing activities until they become exhausted and dysfunctional, a process promoted by cancer cells themselves. Here, we discuss the opposing activities of immune cells populating the tumor microenvironment in both cancer progression and anti-cancer responses, with a focus on cytotoxic T cells and on the molecular mechanisms responsible for the efficient suppression of their killing activities as a paradigm of the power of cancer cells to shape the microenvironment for their own survival and expansion.

Highlights

The most recent studies on cancer onset and development have pointed the spotlight on the intense crosstalk between cancer cells and a heterogeneous population of other cells that reside in the tumor microenvironment (TME) [1]
LAG-3 ligands other than the major histocompatibility complex (MHC) class II were recently identified, which might contribute to immune regulation by triggering or blocking signaling cascades, including fibrinogen-like protein 1, whose upregulated expression correlates with the development of solid tumors [135] and Galectin-3, a 31-kDa lectin that suppresses T cell effector functions via LAG-3 in mice [136]
cytotoxic T lymphocytes (CTLs) and how these mechanisms are made dysfunctional in the specific context of the immunosuppressive TME is expected to result in the development of strategies to deprive

Summary

Introduction

The most recent studies on cancer onset and development have pointed the spotlight on the intense crosstalk between cancer cells and a heterogeneous population of other cells that reside in the tumor microenvironment (TME) [1]. Called non-immune reactive, immune-excluded or immune-desert tumors, produce anti-inflammatory cytokines and have low de novo antigens and few mutations These tumors display low or no immune cell infiltrates and evade host recognition. Sci. 2021, 22, 11221 crosstalk arising in the “hot TME” tunes immune cell transcriptomes and secretomes and rewires their phenotype to either antagonize or promote tumor growth [11] This is clearly exemplified by macrophages, highly represented in the TME, a feature which earned them the name of tumor-associated macrophages (TAMs), that carry out distinct functions depending on signals received from the environment [12] (Figure 1). While on the one hand, NKs kill malignant cells expressing ligands for NK-specific surface receptors, such as the natural killer group 2D (NKG2D) ligand MIC-A [37], on the other hand, they paradoxically select and promote the expansion of neoplastic clones that develop mutations, which reduce the expression of NK-receptor ligands, making them resistant to immune attack [36]

Adaptive Immune Cells

Altered Killing Capacities of CTLs in Cancer

Immune

Conclusions and Perspectives