Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Abstract

Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatments. Among them, immune checkpoint blocking therapy, represented by PD-1/PD-L1 inhibitors (nivolumab) and CTLA-4 inhibitors (ipilimumab), has shown encouraging therapeutic effects in the treatment of various malignant tumors, such as non-small cell lung cancer (NSCLC) and melanoma. In addition, with the advent of CAR-T, CAR-M and other novel immunotherapy methods, immunotherapy has entered a new era. At present, evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect. However, the overall clinical response rate of tumor immunotherapy still needs improvement, which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents. Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future. In this article, we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.

Fig. 1

Historical landmarks in cancer immunotherapy development

Fig. 2

List of immune checkpoint inhibitors and their receptors

Fig. 3

Schematic diagram of the working mechanism of PD-1 antibodies

Fig. 4

Illustration of CTLA-4 and PD-1

Fig. 5

Structure of CAR-T cells

Fig. 6

Workflow of CAR-T therapy

Fig. 7

Workflow of CRISPR technology-based immunotherapy

Fig. 8

Characteristics of M1 and M2 macrophages (Nature Reviews Immunology)

Fig. 9

Multipotent antitumor mechanisms of CAR-M therapy

Fig. 10

Function of MDSCs