Cold atmospheric plasma: Novel opportunities for tumor microenvironment targeting

Abstract

With mounting preclinical and clinical evidences on the prominent roles of the tumor microenvironment (TME) played during carcinogenesis, the TME has been recognized and used as an important onco-therapeutic target during the past decade. Delineating our current knowledge on TME components and their functionalities can help us recognize novel onco-therapeutic opportunities and establish treatment modalities towards desirable anti-cancer outcome. By identifying and focusing on primary cellular components in the TME, that is, tumor-infiltrating lymphocytes, tumor-associated macrophages, cancer-associated fibroblasts and mesenchymal stem cells, we decomposed their primary functionalities during carcinogenesis, categorized current therapeutic approaches utilizing traits of these components, and forecasted possible benefits that cold atmospheric plasma, a redox modulating tool with selectivity against cancer cells, may convey by targeting the TME. Our insights may open a novel therapeutic avenue for cancer control taking advantages of redox homeostasis and immunostasis.

Keywords: cancer-associated fibroblast; cold atmospheric plasma; mesenchymal stem cell; tumor microenvironment; tumor-associated macrophage; tumor-infiltrating lymphocyte.

FIGURE 1

Types of tumor infiltrating lymphocytes and their primary roles in cancer. Primary tumor‐infiltrating lymphocytes (TILs) include CD8⁺ T cells, CD4⁺ T cells, B cells and natural killer (NK) cells, where CD4⁺ T cells are sub‐categorized into Th1, Th2 and Treg cells. CD8⁺ T cells are the primary TILs taking on the cytotoxicity function against cancer cells. Th1 cells and Treg cells take opposite roles, i.e., while Th1 cells activate CD8⁺ T and NK cells, Treg cells suppress them. Th2 cells activate B cells. These TILs can be categorized into four subclasses based on their contributions to anti‐cancer immunity. (A) Cancer‐specific T cells are activated in a T‐cell receptor (TCR)‐dependent way and kill tumor cells upon TCR binding of major histocompatibility complex‐presented antigens. (B) False bystander TILs recognize antigens from both cancer cells and cancer‐unrelated pathogens as they have dual TCRs and viral or bacterial antigens may also be present in tumor cells. (C) Active bystander TILs recognize tumor‐unrelated antigens in response to concurrent infection or in a TCR‐independent manner. (D) Inactive bystander TILs recognize tumor‐unrelated antigens. Both active and inactive bystander TILs do not contribute to the anti‐cancer immunity.

FIGURE 2

Current onco‐therapeutic strategies utilizing properties of primary tumor microenvironment (TME) cellular components. (A) Onco‐therapeutic strategies utilizing tumor‐infiltrating lymphocyte (TIL) properties largely rely on blocking immune checkpoints. (B) Onco‐therapeutic strategies targeting tumor‐associated macrophages (TAMs) either eradicate TAMs or repolarize TAMs from the M2 to the M1 state. (C) Onco‐therapeutic strategies targeting cancer‐associated fibroblasts (CAFs) mainly target myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs). As myCAFs are featured by ‘high α‐SMA and low IL6’ and are activated by TGFβ/SMAD signaling, therapeutics against myCAFs are designed to target the TGFβ/SMAD axis. As iCAFs are characterized by ‘low α‐SMA and high IL6’ and are activated by JAK/STAT signaling, therapeutics killing these cells are designed to target the JAK/STAT axis. Therapeutics have also been proposed to target miRNAs in CAF‐derived exosomes. (D) Onco‐therapeutic strategies targeting mesenchymal stem cells (MSCs) can be either targeting MSCs or their derived exosomes. MSCs of different origins and their derived exosomes can be used for delivering drugs, including chemotherapies, nano‐based chemotherapies, nanoparticles, and oncolytic viruses. MSC‐derived exosomes can also be genetically modified to deliver cytokines, tumor suppressors, or miRNAs to tumors or the TME towards desirable therapeutic outcome.

FIGURE 3

Onco‐therapeutic opportunities of cold atmospheric plasma (CAP) utilizing properties of primary tumor microenvironment (TME) cellular components. (A) For tumor‐infiltrating lymphocytes (TILs), CAP can possibly enhance tumor antigen secretion and enhance CD8⁺ TIL cytotoxicity. (B) For tumor‐associated macrophages (TAMs), CAP can potentially repolarize TAMs from the M2 to the M1 state. (C) For cancer‐associated fibroblasts (CAFs), CAP may modulate p53‐driven CAF hierarchy towards enhanced drug sensitivity. (D) For mesenchymal stem cells (MSCs), CAP may block MSCs differentiation to CAFs that is associated with reduced cancer stemness. (E) CAP can function as the cargo of MSCs or their derived exosomes for enhanced delivery to the tumor loci, where MSCs are not necessarily originated from the TME.