The Cancer Cell Dissemination Machinery as an Immunosuppressive Niche: A New Obstacle Towards the Era of Cancer Immunotherapy

Abstract

Although cancer immunotherapy has resulted in unpreceded survival benefits to subsets of oncology patients, accumulating evidence from preclinical animal models suggests that the immunosuppressive tumor microenvironment remains a detrimental factor limiting benefit for many patient subgroups. Recent efforts on lymphocyte-mediated immunotherapies are primarily focused on eliminating cancer foci at primary and metastatic sites, but few studies have investigated the impact of these therapies on the highly complex process of cancer cell dissemination. The metastatic cascade involves the directional streaming of invasive/migratory tumor cells toward specialized blood vessel intravasation gateways, called TMEM doorways, to the peripheral circulation. Importantly, this process occurs under the auspices of a specialized tumor microenvironment, herewith referred to as “Dissemination Trajectory”, which is supported by an ample array of tumor-associated macrophages (TAMs), skewed towards an M2-like polarization spectrum, and which is also vital for providing microenvironmental cues for cancer cell invasion, migration and stemness. Based on pre-existing evidence from preclinical animal models, this article outlines the hypothesis that dissemination trajectories do not only support the metastatic cascade, but also embody immunosuppressive niches, capable of providing transient and localized immunosubversion cues to the migratory/invasive cancer cell subpopulation while in the act of departing from a primary tumor. So long as these dissemination trajectories function as “immune deserts”, the migratory tumor cell subpopulation remains efficient in evading immunological destruction and seeding metastatic sites, despite administration of cancer immunotherapy and/or other cytotoxic treatments. A deeper understanding of the molecular and cellular composition, as well as the signaling circuitries governing the function of these dissemination trajectories will further our overall understanding on TAM-mediated immunosuppression and will be paramount for the development of new therapeutic strategies for the advancement of optimal cancer chemotherapies, immunotherapies, and targeted therapies.

Extracellular Matrix Biomarkers in Colorectal Cancer

“…During everyday physiologic cellular division, cancer cells can be repeatedly produced [1,2]; however, homeostasis is usually preserved by a healthy microenvironment, which prevents these cells from dividing further. However, with the development of a tumor microenvironment (TME) consisting of tumor vasculature, connective tissue, and infiltrating immune cells [3], cancer cells can then infiltrate, disseminate, and ultimately become metastatic [4]. The extracellular matrix (ECM) is formed by numerous proteins, among which proteoglycan, collagen, and laminin are the main components.…”

Metastatic Breast Cancer Recurrence after Bone Fractures

“…Tissue repair after bone fractures is followed by changes in the immune system (and systemic release of cytokines) [22] that could explain a systemic effect on DTCs even located far away from the fracture site [22,23]. Changes in immune-mediated processes, such as an increase in tumor-promoting M2 macrophages occurring after bone fractures [24][25][26], may promote the growth of DTCs into overt metastases.…”

Mini-Review: Can the Metastatic Cascade Be Inhibited by Targeting CD147/EMMPRIN to Prevent Tumor Recurrence?

“…Such interactions promote the EMT process and increase the ability of tumor cells to migrate and invade ( 65 – 67 ). Perivascular TAMs (identified as Tie2 + VEGFA + MRC1 + ) promote angiogenesis and vascular permeability by enhancing VEGF secretion ( 68 , 69 ), and assist in generating specialized temporal structures (called tumor microenvironment of metastasis-TMEM) that are based on direct cell-cell contacts with both tumor cells and endothelial cells. These TMEMs become the gateways which facilitate the intravasation of the metastatic cells ( 11 , 70 – 72 ).…”