Evaluation of cytotoxic T lymphocyte-mediated anticancer response against tumor interstitium-simulating physical barriers

Abstract

Tumor antigen-specific cytotoxic T lymphocyte (CTL) is a promising agent for cancer therapy. Most solid tumors are characterized by increased interstitial fluid pressure (IFP) and dense collagen capsule, which form physical barriers to impede cancer treatment. However, it remains unclear how CTL-mediated anticancer response is affected at the presence of these obstacles. Using a microfluidic-based platform mimicking these obstacles, we investigated the migration characteristics and performance of anticancer response of CTLs targeting hepatic cancer cells via antigen-specific and allogeneic recognition. The device consisted of slit channels mimicking the narrow interstitial paths constrained by the fibrous capsule and increased IFP was simulated by applying hydrostatic pressure to the tumor center. We found that antigen-specificity of CTLs against the targeted cancer cells determined the cytotoxic efficacy of the CTLs but did not significantly affect the success rate in CTLs that attempted to infiltrate into the tumor center. When increased IFP was present in the tumor center, CTL recruitment to tumor peripheries was promoted but success of infiltration was hindered. our results highlight the importance of incorporating the physical characteristics of tumor interstitum into the development of CTL-based cancer immunotherapy. Tumor antigen-specific CD8 + cytotoxic T lymphocyte (CTL)-mediated killing of tumor cells has a crucial role in cancer immunotherapy 1. Success of CTL-mediated tumor rejection requires the recruitment, infiltration, and expansion of tumor antigen-specific CTLs in tumor interstitium-the fluidic and matrix compartments between vessels and tumor cells, and recognition and killing of the tumor cells by the CTLs 2. However, a large body of evidence indicates that tumor cells actively reprogram surrounding interstitium to restrict CTLs from interacting with the tumor cells 3. For example, many types of cancer upregulate endothelins signalling of tumor endothelium to impede CTLs infiltration in tumor 4,5 ; soluble mediators such as IL-10 and transforming growth factor β (TGF-β) secreted by either tumor cells or tumor-recruited Treg cells significantly suppress the cytotoxic function of CTLs 3. While a multitude of chemical factors employed by cancers to escape from anticancer immunity are disclosed 6 , an increasing interest has recently been gained in the physical barriers established by tumors in their interstitium, which also poses a significant challenge to CTLs to successfully contact the targeting cells 7,8. Direct delivery of immune cells into tumor interior via perfusion may be physically hindered by the increased vascular resistance imposed by the high compressive stress generated by tumor growth 9,10. The growth-induced solid stress is mainly contributed by the collagen network and space-taking molecules, such as hyaluronan, accumulated in the tumor interstitium 11. Strategies to improve the delivery of blood-borne therapeutic agents against tumor, including the anticancer immune cells, has ...

Inflammation-related pyroptosis, a novel programmed cell death pathway, and its crosstalk with immune therapy in cancer treatment

“…Cytotoxic T lymphocytes (CTLs) play a vital role in immunotherapy by recognizing specific antigens on tumor cells 121 . Moreover, CTLs can impose perforin on target cells and deliver granzymes, which leads to pore formation and cytolysis 122 ; this morphology shares similarities with pyroptotic cell death.…”

The solid tumor microenvironment—Breaking the barrier for T cells

“…[34] On the contrary, migration and infiltration of T cells is significantly reduced, once a certain collagen density is reached, [34] in example, when space between the fibrils is smaller than 5 µm. [32] A recent study by Sun et al showed that discoidin domain receptor 1 (DDR1)'s extracellular domain (DDR1-ECD) facilitates collagen fiber alignment, hence immune exclusion. Upon knock-out and capture by monoclonal antibodies specific to DDR1-ECD, T cell invasion was restored, resulting in triple-negative breast cancer remission for 10 out of 18 mice.…”

“…There were also studies using some physical methods (e.g., hyperthermia, [83] and photodynamic therapy [84] ) for the same purpose. Furthermore, Chen et al [32] showed that antigen-specific transmigration of T cells into a microfluidics-based cancer model was stalled under elevated hydrostatic pressure (see Figure 1A). In summary, extravasation only is possible from peripheral well-organized vessels which are exposed to low IFP.…”

The Solid Tumor Microenvironment - Breaking The Barrier For T Cells<strong> </strong>

“…[34] On the contrary, migration and infiltration of T cells is significantly reduced, once a certain collagen density is reached, [34] in example, when space between the fibrils is smaller than 5 µm. [32] A recent study by Sun et al showed that discoidin domain receptor 1 (DDR1)'s extracellular domain (DD1-ECD) facilitates collagen fiber alignment, hence immune exclusion. Upon knock-out and capture by monoclonal antibodies specific to DDR1-ECD, T cell invasion was restored, resulting in triple-negative breast cancer remission for 10 out of 18 mice.…”

“…[76] In a different study, IFP was significantly decreased with the anti-PDGF receptor kinase antibody (imatinib) with similar positive results on patient's survival. [67] Furthermore, Chen et al [32] showed that antigen-specific transmigration of T cells into a microfluidics-based cancer model was stalled under elevated hydrostatic pressure (see Figure 1A). In summary, extravasation only is possible from peripheral well-organized vessels which are exposed to low IFP.…”