Nanomedicine is used in the whole cycle of tumor immunity

Nanomedicine is used in the whole cycle of tumor immunity.  Nanomedicine applied to tumor immune cycle.

1. Promote the release of TAAs

The lack of tumor-associated antigen release is a challenge for immunotherapy.

Nano-drugs deliver immunogenic cell death (ICD) to induce drugs to the immune microenvironment, increase the tumor microenvironment TAAs, and even release them into the blood circulation, where they are recognized by APC cells such as DCs.

In addition, ICD therapy, such as radiotherapy, can also increase tumor tissue perfusion and relieve tissue hypoxia, correct tumor vascular abnormalities, and achieve normalization of tumor tissue. It will also increase the efficacy of immune checkpoint inhibitors.

(Image source: Nat Rev Immunol 2017;17:97–111.)

2. Submission of TAAs

Local delivery activates immune drugs, enhances the activity of APCs, and increases the presentation of TAAs.
Mature DCs can present TAAs to T cells to activate immunity, but immature DCs cannot be effectively presented and may also develop immune tolerance.

The combination of non-nano-drug TLR9 agonists (SD-101) and STING agonists (SD-100) and immune checkpoint drugs, early data show that it increases T cell infiltration and activates cytotoxic T cells and NK cells (Reference 1) . TLR agonist and STING agonist nanomedicine began to show the effect of promoting the maturation of DC cells in animal models (Reference 2).

Deliver immune checkpoint inhibitors, restore depleted T cell activity, and enhance activation after TAAs recognition.

3. Activated T cells such as nano-tumor vaccines

Nanomedicine encapsulates antigens and adjuvants to make nano-tumor vaccines, which are targeted for delivery to activate T cells.

Without nanotechnology, subunit vaccines require repeated local injections, such as the injection of mRNAs into the inguinal lymph nodes and the injection of peptides into the subcutaneous tissue, which may be invasive and lead to antigen tolerance.

Subcutaneous injection of nanomedicine, especially nanomedicine with a diameter of 10-100nm, enables the vaccine to be more effectively delivered and retained in the draining lymph nodes, and promotes the controlled release of antigens and adjuvants, thereby increasing the level of antigen presentation.

Second, use the targeting group of the nano-vaccine or adjust its physicochemical properties to increase the uptake of the nano-vaccine by DC and other APCs.

Third, nano-vaccine can promote antigen cross-presentation and increase the level of CTL activation. Otherwise, when exposed to conventional vaccines, T cells will tilt toward the CD4 phenotype.

Specifically, nano-vaccine promotes the release of endosomes through a pH-sensitive delivery system that releases antigens in endosomes. This allows APC to engulf the antigens and present them to CTL by MHC class I molecules, while traditional vaccines rely on MHC class II molecules. Extracellular antigens (soluble proteins or peptides) presented to CD4 T cells.

Fourth, nano-vaccine can deliver antigen and adjuvant together, which increases antigen presentation and cross presentation, and promotes the development of CD4T-assisted anti-tumor phenotype.

4. Normalization of tumor microenvironment increases T cell infiltration

Nanomedicine usually has a limited level of distribution in tumors, because the tumor microenvironment (TME) restricts blood flow, thus limiting the degree of penetration of nanomedicine tumors.

TME standardized therapy increases and homogenizes the intratumoral distribution of immune cells and nanomedicine. Nano-drug-based vaccines and self-transferred T cells carrying nano-drugs increase the number of anti-tumor T cells in the host. If TME is normalized, a greater proportion of T cells can migrate to the tumor parenchyma. Similarly, the functionalized nanomedicine after TME normalization can penetrate the tumor parenchyma at a higher rate. Therefore, the normalization of TME can improve the effectiveness of targeted nanomedicine combined with cytotoxic drugs and immunotherapy.

5. Increase T cells to recognize tumors

In addition to delivering antigens and immune activating compounds to APC to promote the response of memory T cells to tumors, nanomedicine can also be designed to promote the recognition of cancer cells by infiltrating T cells.
For example, nano-drugs are conjugated to HER2 antibody and calreticulin (providing phagocytic signals). This multivalent bi-specific nanobioconjugate engager (mBiNE) can target tumors through HER2 antibodies and use macrophages to target tumors. The phagocytosis of tumor cells releases and presents TAAs to T cells, promotes T cell activation, becomes effector cells, and kills tumor cells.

Picture from literature 3

6. Kill tumor cells

If a tumor immune cycle cannot completely kill tumor cells, it may be suppressive signals such as immune checkpoints, IDO, and suppressive immune cells that inhibit the final killing effect. Therefore, inhibitors such as immune checkpoints and IDO can restore T cell activity and continue to perform killing functions. Nevertheless, in a phase III trial involving patients with unresectable or metastatic melanoma, pembrolizumab combined with IDO inhibitors failed to provide any improvement in efficacy (Reference 4). Now nanomedicine is also beginning to experiment in this regard.

Picture from literature 5

Expert comments:

Nanomedicine targets the antibody through the surface, while adjusting the physical and chemical properties, increasing its ability to target the drug delivery and sustained release. Avoiding the systemic toxicity of traditional drug delivery and increasing the local drug concentration of the tumor has its unique characteristics. Combining classic anti-tumor drugs and antibody drugs, it can be applied to the entire tumor immune cycle.

(source:internet, reference only)

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