Advancing to the era of cancer immunotherapy

Abstract

Cancer greatly affects the quality of life of humans worldwide and the number of patients suffering from it is continuously increasing. Over the last century, numerous treatments have been developed to improve the survival of cancer patients but substantial progress still needs to be made before cancer can be truly cured. In recent years, antitumor immunity has become the most debated topic in cancer research and the booming development of immunotherapy has led to a new epoch in cancer therapy. In this review, we describe the relationships between tumors and the immune system, and the rise of immunotherapy. Then, we summarize the characteristics of tumor-associated immunity and immunotherapeutic strategies with various molecular mechanisms by showing the typical immune molecules whose antibodies are broadly used in the clinic and those that are still under investigation. We also discuss important elements from individual cells to the whole human body, including cellular mutations and modulation, metabolic reprogramming, the microbiome, and the immune contexture. In addition, we also present new observations and technical advancements of both diagnostic and therapeutic methods aimed at cancer immunotherapy. Lastly, we discuss the controversies and challenges that negatively impact patient outcomes.

Keywords: adverse effects; cancer; hyperprogressive disease; immune checkpoints; immunity; immunotherapy; metabolic reprogramming; microbiome; mutation.

FIGURE 1

Variable interactions among immune checkpoints in the TME. There are many immune checkpoints in the TME. Some of them are expressed mainly on T cells including PD‐1, CTLA‐4, and LAG‐3, which could suppress the function of CTLs. The others are mainly expressed on myeloid cells, such as c‐Rel and MerTK, which could enhance the inhibitory function of MDSCs to tumor cells. Abbreviations: TME: tumor microenvironment; CTLs: cytotoxic T lymphocytes; IL: interleukin; CD: cluster of differentiation; MHC: major histocompatibility complex; PD‐1: programmed cell death‐1; PD‐L1: programmed cell death‐Ligand 1; PD‐L2: programmed cell death‐Ligand 2; CTLA‐4: cytotoxic T lymphocyte‐associated antigen 4; VISTA: V‐domain immunoglobulin suppressor of T cell activation; TIGIT: T cell immunoglobulin and ITIM domain; TIM‐3: T cell immunoglobulin and mucin domain‐containing protein 3; LAG‐3: lymphocyte activation gene‐3; ATP: adenosine triphosphate; AMP: adenosine monophosphate; GPI: glycosylphosphatidylinositol; SIRPα: signal regulatory protein α; SIGLEC‐15: sialic acid binding Ig‐like lectin 15; GM‐CSF: granulocyte‐macrophage colony stimulating factor; IL‐RAcP: interleukin‐1 receptor accessory protein; ST2: suppression of tumorigenicity 2; MERTK: c‐mer proto‐oncogene tyrosine kinase; GAS6: growth arrest specific 6; PtdSer: phosphatidylserine; TCR: T cell receptor; SIGLEC‐10: sialic acid binding Ig‐like lectin 10; VSIG‐3: V‐set and immunoglobulin domain‐containing protein 3; LGALS9: galectin‐9; DAP12: DNAX‐activation protein 12; sTn: sialyl‐Tn; PI3K: phosphoinositide 3‐kinase; ARG1: arginase‐1; NOS2: nitric oxide synthase 2

FIGURE 2

Metabolic interactions in the TME are based on the basic status of the patient. Food is digested and decomposed into metabolites and nutrients based on the basic metabolic status of the human body. The intestinal microbiome participates in the metabolism of these small molecules and influences their levels in the blood. Then, the metabolites and nutrients are sent to the tumor site, forming a competition for nutrients between tumor cells and immune cells in the TME, which is also affected by the local microbiome. Abbreviations: TME: tumor microenvironment

FIGURE 3

The balance between response and toxicity in anti‐PD therapy compared with other immunotherapy methods. Toxicity outweighs the response in immunotherapy methods such as IL‐2, IFNs, CAR‐T cells, and anti‐CTLA‐4 antibodies, resulting in quite limited indications. For anti‐PD therapy, the response outweighs toxicity considerably, which leads to a rather broad application. Abbreviations: CAR‐T: chimeric antigen receptor T cells; CTLA‐4: cytotoxic T lymphocyte‐associated antigen 4; IFN: interferon; IL‐2: interleukin‐2; PD: programmed death

FIGURE 4

Adding a limited course of chemotherapy to immunotherapy to address HPD. Accelerated disease progression due to HPD significantly compromised the total survival benefit of anti‐PD therapy over chemotherapy, which could be rescued by adding a limited course of chemotherapy to anti‐PD therapy. Abbreviations: HPD: hyperprogressive disease; PD: programmed death