Targeting Cellular Components of the Tumor Microenvironment in Solid Malignancies

Abstract

Cancers are composed of transformed cells, characterized by aberrant growth and invasiveness, in close relationship with non-transformed healthy cells and stromal tissue. The latter two comprise the so-called tumor microenvironment (TME), which plays a key role in tumorigenesis, cancer progression, metastatic seeding, and therapy resistance. In these regards, cancer-TME interactions are complex and dynamic, with malignant cells actively imposing an immune-suppressive and tumor-promoting state on surrounding, non-transformed, cells. Immune cells (both lymphoid and myeloid) can be recruited from the circulation and/or bone marrow by means of chemotactic signals, and their functionality is hijacked upon arrival at tumor sites. Molecular characterization of tumor-TME interactions led to the introduction of novel anti-cancer therapies targeting specific components of the TME, such as immune checkpoint blockers (ICB) (i.e., anti-programmed death 1, anti-PD1; anti-Cytotoxic T-Lymphocyte Antigen 4, anti-CTLA4). However, ICB resistance often develops and, despite the introduction of newer technologies able to study the TME at the single-cell level, a detailed understanding of all tumor-TME connections is still largely lacking. In this work, we highlight the main cellular and extracellular components of the TME, discuss their dynamics and functionality, and provide an outlook on the most relevant clinical data obtained with novel TME-targeting agents, with a focus on T lymphocytes, macrophages, and cancer-associated fibroblasts.

Chemokines as possible therapeutic targets in metastatic melanoma

“…36 Upon interaction with APC, CD8+ T cells have the ability to differentiate into cytotoxic T lymphocytes (CTLs), which destroy tumour cells in the tumour microenvironment by releasing perforin and granzyme B. 34 In contrast, pro-tumour effector cells include tumourassociated macrophages (TAMs), myeloid-derived suppressor cells (MDSC), tumour-associated neutrophils (TANs) and regulatory T cells (Treg). 37 TAMs are found in cutaneous melanoma and in several non-melanoma skin cancers.…”

“…37 MDSCs and TANs suppress T cells and NK cells and recruit Treg cells, which suppress T cell responses and promote cancer immune evasion and escape. 34,35 However, the crosstalk between signalling pathways and immune responses presents a complex and dynamic system in the context of cancer development and progression within the tumour microenvironment. Therefore, the involvement of governing chemokine axes in the promotion of cutaneous and metastatic melanoma demands a proper understanding of the tumour microenvironment in order to identify possible targets and develop appropriate treatments against melanoma.…”

“…Chemokines recruit various immune cells, such as natural killer (NK) cells, cDC1 s, Th1 cells, and CD8+ T cells from the blood to the tumour microenvironment. NK cells, CD4+ T helper type 1 (Th1) cells and CD8+ T cells, can directly lyse cancer cells or produce cytokines to eradicate tumour cells 31,34 . As a result, NK cells are often associated with good prognosis in cancer patients 35 .…”

“…Furthermore, in many skin cancers, including melanoma, TAMs may directly produce immunosuppressive chemokines, 31 which may attract other immunosuppressive cells, including MDSCs, Tregs and TANs 37 . MDSCs and TANs suppress T cells and NK cells and recruit Treg cells, which suppress T cell responses and promote cancer immune evasion and escape 34,35 …”

From Dual Roles to Translational Challenges: Unpacking the Complexities of Tumor-Associated Macrophages in Cancer Progression and Therapy

“…Colony-stimulating factor 1 receptor (CSF1R) is a class III receptor tyrosine kinase that is expressed on TAM and is a promising therapeutic target in Oncology since it is involved in the proliferation and survival of TAMs [156,157]. Inhibitors of CSF1R are being developed and tested in clinical trials for the treatment of various types of cancer, including a Phase 2 clinical trial investigating the CSF1R inhibitor pexidartinib in combination with pembrolizumab for advanced melanoma [11,[158][159][160]. There are currently 20 ongoing clinical trials related to CSF1R in cancer patients that are in the recruiting phase.…”