Next-Generation Immunotherapies to Improve Anticancer Immunity

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.

Interleukin-8 in Melanoma Pathogenesis, Prognosis and Therapy—An Integrated View into Other Neoplasms and Chemokine Networks

“…Both Paclitaxel and blockade of IL-8Rs were separately used in melanoma therapy, so such a combinatorial would be expected successful in melanoma too. Additional chemotaxis inhibitors, as those targeting CXCR2, an important marker for neutrophil migration from bone marrow into site of inflammation, in combinations withother inhibitors of CKs/CKRs (e.g., CXCL12/CXCR4 or CCR5-maraviroc) are under investigation to hinder the recruitment of neutrophils to the TME [ 212 , 213 ]. TAMs —Numerous studies showed that TAMs which favor tumor progression resemble to macrophage M2 phenotypes [ 214 ].…”

Optimizing NK Cell-Based Immunotherapy in Myeloid Leukemia: Abrogating an Immunosuppressive Microenvironment

“…Tumor-infiltrating NK cells exhibit poor cytotoxic capacity, accompanied by downregulation of activating receptors, upregulation of inhibitory receptors, and upregulation of immune checkpoint receptors, compared with NK cells from healthy tissues (103). The development of novel approaches such as monoclonal antibodies (mAbs) to block inhibitory receptors enhances NK cell function and its anti-tumor capacity (104). Despite efforts to combat immunosuppressive effects, multiple factors in the TME still limit NK cell function.…”

Blockade of neutrophil recruitment to tumor sites based on sialic acid-modified nanoplatforms enhances the efficacy of checkpoint blockade immunotherapy

“…In recent years, ICIs have made revolutionary breakthroughs in the treatment of a variety of advanced solid tumors [ 1 , 2 ]. However, studies have found that the inhibition rate of ICIs in solid tumors is only 10%–40% [ 3 , 4 ], which indicates that a large number of patients cannot benefit from immunotherapy. In addition, ICIs technology has been stagnant in the area breast cancer treatment, because breast cancer was previously considered to be a "cold tumor" with low immunogenicity [5] .…”