Cold Tumors: A Therapeutic Challenge for Immunotherapy

Abstract

Therapeutic monoclonal antibodies targeting immune checkpoints (ICPs) have changed the treatment landscape of many tumors. However, response rate remains relatively low in most cases. A major factor involved in initial resistance to ICP inhibitors is the lack or paucity of tumor T cell infiltration, characterizing the so-called "cold tumors." In this review, we describe the main mechanisms involved in the absence of T cell infiltration, including lack of tumor antigens, defect in antigen presentation, absence of T cell activation and deficit of homing into the tumor bed. We discuss then the different therapeutic approaches that could turn cold into hot tumors. In this way, specific therapies are proposed according to their mechanism of action. In addition, ''supra-physiological'' therapies, such as T cell recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, may be active regardless of the mechanism involved, especially in MHC class I negative tumors. The determination of the main factors implicated in the lack of preexisting tumor T cell infiltration is crucial for the development of adapted algorithms of treatments for cold tumors.

Keywords: T cells; cold tumors; immunotherapy; presentation; priming; trafficking; tumor antigen.

Figure 1

Reversing a cold into a hot tumor. Adapted from Chen and Mellman (1). The absence of T cells in the tumor can be due to the lack of tumor antigens, APC deficit, absence of T cell priming/activation and impaired trafficking of T cells to the tumor mass (left panel). Understanding which step of the anti-cancer immune response is not functional in cancers is crucial to adapt therapies to the cancer phenotype.

Figure 2

Specific and common approaches to overcome the absence of T cells in tumors. According to the mechanism involved in the lack of T cell infiltration in tumors, specific therapies can be selected. In the case of MHC-I negative tumors or if specific therapies are not sufficient, “supra-physiological therapies” can be used.