Abstract
Checkpoint inhibitors are widely used immunotherapies for advanced cancer. Nonetheless, checkpoint inhibitors have a relatively low response rate, work in a limited range of cancers, and have some unignorable side effects. Checkpoint inhibitors aim to reinvigorate exhausted or suppressed T cells in the tumor microenvironment (TME). However, the TME contains various other immune cell subsets that interact to determine the fate of cytotoxic T cells. Activation of cytotoxic T cells is initiated by antigen cross-presentation of dendritic cells. Dendritic cells could also release chemokines and cytokines to recruit and foster T cells. B cells, another type of antigen-presenting cell, also foster T cells and can produce tumor-specific antibodies. Neutrophils, a granulocyte cell subset in the TME, impede the proliferation and activation of T cells. The TME also consists of cytotoxic innate natural killer cells, which kill tumor cells efficiently. Natural killer cells can eradicate major histocompatibility complex I-negative tumor cells, which escape cytotoxic T cell–mediated destruction. A thorough understanding of the immune mechanism of the TME, as reviewed here, will lead to further development of more powerful therapeutic strategies. We have also reviewed the clinical outcomes of patients treated with drugs targeting these immune cells to identify strategies for improvement and possible immunotherapy combinations.
Highlights
Cancer immunotherapy harnesses the patient’s own immune system to fight against cancer, distinguishing immunotherapy from conventional cancer therapies, which directly target the tumor cells
The preclinical discovery of immune cell subsets and associated cytokines significantly furthered the clinical practice of cancer immunotherapy (Old et al, 1959; Carswell et al, 1975; Herberman et al, 1975; Quesada et al, 1984)
We describe four of these immune cell types, i.e., dendritic cells (DCs), natural killer (NK) cells, B cells, and neutrophils, along with current methods to target these cells to induce antitumor immune activation (Figure 2)
Summary
Cancer immunotherapy harnesses the patient’s own immune system to fight against cancer, distinguishing immunotherapy from conventional cancer therapies, which directly target the tumor cells. Various human STING agonists such as ADUS100 and MK-1454, which may have promising clinical outcomes, were developed and are currently being tested in combination with checkpoint inhibitors in ongoing clinical trials (NCT02675439, NCT03172936, NCT03010176) Another suppressive factor in the TME that results in DC anergy is the “do not eat me” molecules expressed on tumor cells. Multiple phase I/II clinical trials in patients with solid tumors or hematologic malignancies are ongoing for these checkpoint inhibitors, including anti-TIM3 (e.g., NCT03489343), anti-LAG3 (e.g., NCT03005782), and antiTIGIT (e.g., NCT04354246), as well as combination therapies, such as the combination of anti-TIM3, anti-PD-1, and anti-LAG3 (NCT04370704) and the combination of anti-LAG3 with antiTIGIT (NCT04150965). Considering the multiple roles of tumor-infiltrating B cells in tumor immunity, B cell depletion therapy, and selective clearance of regulatory B cells, promoting TLS formation and targeted regulation of tumor-infiltrating B cell-linked signaling pathways may become effective strategies for tumor-infiltrating B-cell-based tumor immunotherapy
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