Therapeutic Targets and Tumor Microenvironment in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is a genetically, anatomically, and transcriptionally heterogeneous disease. The prognosis for a CRC patient depends on the stage of the tumor at diagnosis and widely differs accordingly. The tumor microenvironment (TME) in CRC is an important factor affecting targeted cancer therapy. The TME has a dynamic composition including various cell types, such as cancer-associated fibroblasts, tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, as well as extracellular factors that surround cancer cells and have functional and structural roles under physiological and pathological conditions. Moreover, the TME can limit the efficacy of therapeutic agents through high interstitial pressure, fibrosis, and the degradation of the therapeutic agents by enzymatic activity. For this reason, the TME is a fertile ground for the discovery of new drugs. The aim of this narrative review is to present current knowledge and future perspectives regarding the TME composition based on strategies for patients with CRC.

Keywords: angiogenesis; cancer-associated fibroblasts; colorectal cancer; regulatory T cells; targeted therapy; tumor microenvironment; tumor-associated macrophages.

Figure 1

Tumor microenvironment interactions. A macroscopic view of the molecular crosstalk between cancer-associated fibroblasts, endothelial vasculature, infiltrating immune cells, and malignant cells in the TME. Dynamic interactions governed by heterotypic signaling mechanisms between cell types modulate various stages of cancer progression (grey boxes). The role of exosomes in this cell-cell signaling is highlighted (blue and orange boxes). From Li et al. [7].

Figure 2

Part I: Clinical Trials of Agents Designed to Target Tumor Stroma. From Fridman et al [9].

Figure 3

Part II: Clinical Trials of Agents Designed to Target Tumor Stroma. From Fridman et al [9].

Figure 4

The consensus molecular subtypes. CMS1 and CMS4 tumors are highly infiltrated by immune cells, whereas CMS1 tumors are characterized by a Th1-cell response and activated and inflamed TME. These tumors can be treated with immune checkpoint inhibitors. CMS4 tumors have an inflamed, complement-rich, suppressive, and highly angiogenic TME that can be targeted with combination therapies. CMS2 tumors do not activate an antitumor immune response due to activation of the b-catenin pathway, and CMS3 tumors are considered to be metabolic tumors. CMS1 (14% of colorectal tumors); CMS2 (37% of colorectal tumors); CMS3 tumors (13% of colorectal tumors); CMS4 tumors (23% of colorectal tumors). From Fridman et al. [9].

Figure 5

Targeting strategies to eliminate or modulate Treg functions. Available antibodies, small molecules, or vaccines specific for different cell surface or intracellular targets. From Laplagne et al. [61].

Figure 6

Targeting strategies to reprogram, eliminate, and inhibit TAM recruitment. Antibodies or molecules available to target surface, intracellular or soluble molecules involved in the phenotype, functions, and recruitment in the TME. From Laplagne et al. [61].

Figure 7

Stages of myelopoiesis differentiation in cancer. Myelopoiesis is amplified during chronic inflammation to assist tumour progression and dissemination. The hematopoietic stem cells (HSC) differentiate into the common myeloid progenitor (CMP), which can further differentiate through the hematopoietic system. In physiological conditions, CMP can differentiate into neutrophils or into monocytes, and subsequently into dendritic cells (DC) or macrophages. However, with chronic inflammation, pro-inflammatory cytokines can skew the monocytopoiesis of CMP into monocytic-myeloid-derived suppressor cells (M-MDSC) and tumour-associated macrophages (TAM), and granulopoiesis into polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and tumour-associated neutrophils (TAN). From Law et al [87].

Figure 8

Treatments used to target different mechanisms associated with pro-tumourigenic MDSC. There are multiple therapeutic approaches against MDSC to restore anti-tumour functions in immune cells and improve immunotherapy, in particular checkpoint inhibitors. These approaches include: (1) depleting MDSC populations through low-dose chemotherapy and tyrosine kinase inhibitors; (2) preventing MDSC recruitment to the TME by targeting chemokine receptors responsible for the recruitment and migration of MDSCs; (3) attenuating the immunosuppressive mechanisms of MDSC by downregulating the expression of ARG1 and iNOS, and reducing ROS generation; (4) inducing the differentiation of MDSC into mature myeloid cells to reduce MDSC population and remove their immunosuppression. From Law et al [87].