Lighting Up the Fire in the Microenvironment of Cold Tumors: A Major Challenge to Improve Cancer Immunotherapy

Abstract

Immunotherapy includes immune checkpoint inhibitors (ICI) such as antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death protein/programmed death ligand 1 (PD-1/PD-L1) axis. Experimental and clinical evidence show that immunotherapy based on immune checkpoint inhibitors (ICI) provides long-term survival benefits to cancer patients in whom other conventional therapies have failed. However, only a minority of patients show high clinical benefits via the use of ICI alone. One of the major factors limiting the clinical benefits to ICI can be attributed to the lack of immune cell infiltration within the tumor microenvironment. Such tumors are classified as "cold/warm" or an immune "desert"; those displaying significant infiltration are considered "hot" or inflamed. This review will provide a brief summary of different tumor properties contributing to the establishment of cold tumors and describe major strategies that could reprogram non-inflamed cold tumors into inflamed hot tumors. More particularly, we will describe how targeting hypoxia can induce metabolic reprogramming that results in improving and extending the benefit of ICI.

Keywords: hypoxia; immune checkpoint inhibitors; immunotherapy; metabolic reprogramming; tumor microenvironment.

Figure 1

The different steps of the cancer-immunity cycle. Briefly, the first step of the cycle consists of releasing antigens from tumor cells (1). These antigens are captured by dendritic cells on MHC-I and MHC-II molecules (2) and presented to T cells (3). This step results in T cell priming and activation in lymph nodes. Activated T cells migrate through the blood vessels to infiltrate the tumor microenvironment (4). Defects in several steps in the cancer-immunity cycle results in the establishment of cold tumors (reported in red).

Figure 2

Summary of the different strategies involved in switching cold into hot tumors and their mode of action. Combining these strategies with immunotherapy improves the therapeutic benefit in cancer patients.

Figure 3

Summary of the mechanisms involved in HIF-1α regulation in normoxia and hypoxia.