Chemo-Immunotherapy: A New Trend in Cancer Treatment

Abstract

Chemotherapy has been the basis of advanced cancer treatment for decades. This therapy has largely been considered immunosuppressive, yet accumulated preclinical and clinical evidence shows that certain chemotherapeutic drugs, under defined conditions, may stimulate antitumor immunity and potentiate immune checkpoint inhibitor (ICI)-based therapy. Its effectiveness has been highlighted by recent regulatory approvals of various combinations of chemotherapy with ICIs in several tumors, particularly in some difficult-to-treat cancers. This review discusses the immune modulatory properties of chemotherapy and how they may be harnessed to develop novel chemo-immunotherapy combinations. It also highlights the key determinants of the success of chemo-immunotherapy and provides an overview of the combined chemo-immunotherapies that have been clinically approved.

Keywords: NK cell; PD-1; T cell; chemotherapy; immune checkpoints; immunotherapy.

Figure 1

Main immunomodulatory effects of chemotherapeutic drugs. The drugs included in the figure may boost antitumor immunity by targeting immunosuppressive immune cells (mostly Tregs and MDSCs), activating NK cells, causing ICD, and stimulating antigen (Ag) presentation through dendritic cells and T cell activity. The dose of the drug seems to play a crucial role in its capability to stimulate the immune system.

Figure 2

Immunogenic cell death (ICD). Chemotherapeutic drugs may induce the immunogenic death of tumor cells, which results in a CD8 T cell-mediated response against tumor antigens expressed by the dying cells. ICD leads to the exposure and release of DAMPs into TME, which are mainly recognized by DCs. Some DAMPs, including ATP and annexin 1 (ANXA1), induce the recruitment of DCs; others, such as calreticulin, are expressed on the membrane of tumor cells acting as an “eat-me signal” enabling their uptake by DCs. The release of HGMB1, type I interferons, and several cytokines and chemokines culminate in the maturation of DCs and the recruitment and activation of antitumor CD8 T cells that mediate the response against the tumor and generate long-term immune memory.