The Immune Microenvironment: A Major Player in Human Cancers

Abstract

Cancer is a major public health issue and figures among the leading causes of death in the world. Cancer development is a long process, involving the mutation, amplification or deletion of genes and chromosomal rearrangements. The transformed cells change morphologically, enlarge, become invasive and finally detach from the primary tumor to metastasize in other organs through the blood and/or lymph. During this process, the tumor cells interact with their microenvironment, which is complex and composed of stromal and immune cells that penetrate the tumor site via blood vessels and lymphoid capillaries. All subsets of immune cells can be found in tumors, but their respective density, functionality and organization vary from one type of tumor to another. Whereas inflammatory cells play a protumoral role, there is a large body of evidence of effector memory T cells controlling tumor invasion and metastasis. Thus, high densities of memory Th1/CD8 cytotoxic T cells in the primary tumors correlate with good prognosis in most tumor types. Tertiary lymphoid structures, which contain mature dendritic cells (DC) in a T cell zone, proliferating B cells and follicular DC, are found in the tumor stroma and they correlate with intratumoral Th1/CD8 T cell and B cell infiltration. Eventually, tumors undergo genetic and epigenetic modifications that allow them to escape being controlled by the immune system. This comprehensive review describes the immune contexture of human primary and metastatic tumors, how it impacts on patient outcomes and how it could be used as a predictive biomarker and guide immunotherapies.

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

“…63 In contrast to primary tumors, we found a significant correlation between LECs and FoxP3 + lymphocytes. The question of whether regulatory T cells play an important role in melanoma progression and metastasis formation is still unanswered, and conflicting data have been reported with regard to clinical impact.…”

Plasma cells in primary melanoma. Prognostic significance and possible role of IgA

“…TLS are inducible and transient structures that occur in non-lymphoid organs, and that share with SLO the same cytokines involved in their genesis, and the same B and T topography. 22 TLS are composed of T-areas containing mature dendritic cells and B-areas containing germinal centers with evidence of isotype switching in B cells; in addition, TLS possess PNAd+HEV and express a range of cytokines important for the organization of SLO. 42 Not all these features are present at the same time, suggesting evolution over time of TLS.…”

“…This has been demonstrated for macrophages (M1 and M2 polarization), [8][9][10][11] neutrophils (N1 and N2 polarization) 12,13 and T lymphocytes (Th1, Th2, Th17 responses). [14][15][16] The role of T lymphocytes and macrophages has been extensively studied in melanoma, 13,[17][18][19][20][21][22] whereas less is known on the role of B lymphocytes and plasma cells (PCs). Recently, B lymphocytes have turned out to constitute between 0 and 50% of the tumor-infiltrating lymphocytes, [23][24][25] but controversy exists as to their precise role in melanoma progression.…”

Role of liver ICAM-1 in metastasis

“…Additionally, these proteins may also act as signaling molecules to modulate the local microenvironment, creating a pro-metastatic environment, and trigger an angiogenic and desmoplastic response via a complex reciprocal dialogue between the tumor cells and the cells of the colonized organ (15,16). In addition to the tissue cells, immune populations recruited from the circulation during metastasis formation are also involved in generating a favorable environment for metastatic growth (17,18). Therefore, determining the role of adhesion molecules during the different stages of this process remains a major goal for our understanding of the metastatic cascade.…”