Establishment of immune suppression by cancer cells in the tumor microenvironment

Abstract

With the clinical success of immune checkpoint inhibitors (ICIs), cancer immunotherapy has become an important pillar of cancer treatment in various types of cancer. However, more than half of patients fail to respond to ICIs, even in combination, uncovering a limited window of clinical responses. Therefore, it is essential to develop more effective cancer immunotherapies and to define biomarkers for stratifying responders and nonresponders by exploring the immunological landscape in the tumor microenvironment (TME). It has become clear that differences in immune responses in the TME determine the clinical efficacy of cancer immunotherapies. Additionally, gene alterations in cancer cells contribute to the development of the immunological landscape, particularly immune suppression in the TME. Therefore, integrated analyses of immunological and genomic assays are key for understanding diverse immune suppressive mechanisms in the TME. Developing novel strategies to control immune suppression in the TME from the perspective of immunology and the cancer genome is crucial for effective cancer immunotherapy (immune-genome precision medicine).

Keywords: cancer immunotherapy; immune checkpoint inhibitors; immune suppression; immune-genome precision medicine; tumor microenvironment.

Figure 1.

Modification of the cancer immunoediting hypothesis. The relationship between cancer cells and the immune system is divided into three phases: elimination phase, equilibrium phase, and escape phase. Immune selection (primary resistance) and immune escape (adaptive resistance), which are involved in the equilibrium and escape phases of cancer immune editing, become activated, leading to carcinogenesis. In humans, these mechanisms are thought to operate in overlapping rather than sequential order.

Figure 2.

Effects of genetic alterations in cancer cells on the immune system. A summary of the effects of genetic abnormalities in cancer cells on the immune system. Some genetic alterations in cancer cells are recognized by the immune system, especially CD8⁺ T cells, as neoantigens. On the other hand, they are also directly involved in the infiltration and activation of immunosuppressive cells in the TME through various mechanisms.

Figure 3.

The concept of immune-genome precision medicine. The TME differs for each patient. Therefore, it is important to clarify the key mechanisms suppressing tumor antigen-specific CD8⁺ T cells in each cancer patient. If Treg cells are a key mechanism for immunosuppression, Treg cell-targeted therapy needs to be combined with PD-1 blockade. In TAM-rich cancer, use of innate immunity-targeted therapy is reasonable. For immunologically cold tumors, comprehensive cancer immunotherapy may be needed.