Mesoporous silica nanoparticles inflame tumors to overcome anti-PD-1 resistance through TLR4-NFκB axis

Abstract

BackgroundThe clinical benefits of antiprogrammed cell death protein 1 (PD-1) therapy are compromised by resistance in immunologically cold tumors. Convergence of immunotherapy and bioengineering is potential to overcome the resistance. Mesoporous silica nanoparticles (MSNs) are considered the most promising inorganic biological nanomaterials for clinical transformation, however, the fundamental influence of MSNs on immunotherapy is unclear. In this study, we aimed to investigate the role of MSNs in tumor resensitization and explore the feasibility of MSNs combined with anti-PD-1 in cancer therapy.MethodsIntrinsic and acquired resistant tumors, as well as spontaneous and secondary tumor recurrence models, were used to evaluate the influence of MSNs and the synergistical effect with anti-PD-1 therapy. The roles of CD8+ cytotoxic T-lymphocytes (CTLs) and macrophages were assessed in Rag-1-/- mice, ovalbumin/OT-1 TCR transgenic T-cell system, and other blocking mice models. Mechanistic studies were processed by transcriptomics analysis and conducted in primary cells, in vitro coculture systems, and Toll-like receptor 4 (TLR4) knockout mice.ResultsBoth granular and rod-shaped MSNs efficiently overcame tumor resistance with dependence on diameter and aspect ratio. Only once injection of MSNs in prior to anti-PD-1 markedly improved the treatment efficacy, protective immunity, and prognosis. MSNs per se boosted infiltration of CTLs as the early event (days 2–3); and synergistically with anti-PD-1 therapy, MSNs rapidly established a T cell-inflamed microenvironment with abundant high-activated (interferon-γ/tumor necrosis factor-α/Perforin/GranzymeB) and low-exhausted (PD-1/lymphocyte-activation gene 3 (LAG-3)/T-cell immunoglobulin and mucin-domain containing-3 (TIM-3)) CTLs. Chemokines Ccl5/Cxcl9/Cxcl10, which were produced predominantly by macrophages, promoted MSNs-induced CTLs infiltration. MSNs led to high Ccl5/Cxcl9/Cxcl10 production in vitro and in mice through regulating TLR4-NFκB axis. Blocking TLR4-NFκB axis in macrophages or CTLs infiltration abrogated MSNs-induced resensitization to anti-PD-1 therapy.ConclusionsMSNs efficiently and rapidly inflame immunologically cold tumors and resensitize them to anti-PD-1 therapy through TLR4-NFκB-Ccl5/Cxcl9/Cxcl10 axis. MSNs-based theranostic agents can serve as sensitizers for patients with resistant tumors to improve immunotherapy.

Differential Expression of the TLR4 Gene in Pan-Cancer and Its Related Mechanism

“…Recent studies have shown that silica nanoparticles promote the tumor infiltration of CD8+ cytotoxic T lymphocytes (CTLs) by targeting the TLR4 /NF-κB pathway. Through PD-1 blockade, the depletion of CTLs is activated and reversed, thereby generating durable antitumor immunity ( Sun et al, 2021 ). Recent findings in chronic inflammatory diseases and cancer indicate that T-cell failure and lymphopenia may be related to changes in the expression level of TLR4 ( Wild et al, 2012 ).…”

Mechanisms of tumor resistance to immune checkpoint blockade and combination strategies to overcome resistance

“…It is also noteworthy that biomaterials at the nanoscale have been explored to establish a T-cell-inflamed TME and overcome resistance to ICB. Mesoporous silica nanoparticles were reported to elicit T-cell-recruitment chemokine production and drive CTL infiltration in multiple tumor models resistant to PD-1 antibodies ( 149 ). A supramolecular gold nanorod has been reported to reprogram the TME and improve TILs, significantly augmenting ICB therapy, which depends on the hyperthermal activation of ICD and genome editing of PD-L1 ( 209 ).…”

Tuning Mesoporous Silica Nanoparticles in Novel Avenues of Cancer Therapy

“…Chemokines Ccl5/Cxcl9/Cxcl10 released by macrophages encouraged MSN-induced CTL infiltration and blockade of the TLR4-NFκB axis in macrophages or CTL revoked MSNinduced resensitization to anti-PD-1 therapy. 182 Chandra and colleagues prepared manganese (Mn 4+ )-doped silica nanoparticles (Mn 4+ -SNP) with a large pore size to incorporate the viral neoantigen peptide GF001 obtained from HPV16 E7 oncoprotein. They revealed that Mn 4+ -SNP acted as selfadjuvants via ROS generation, dendritic cell stimulation, and maturation.…”

“…MSN aided in the prompt development of a T cell-inflamed microenvironment with the stimulation of interferon-γ/tumor necrosis factor-α/perforin/granzyme B with little effect on PD-1/lymphocyte-activation gene 3 (LAG-3)/T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) CTL. Chemokines Ccl5/Cxcl9/Cxcl10 released by macrophages encouraged MSN-induced CTL infiltration and blockade of the TLR4-NFκB axis in macrophages or CTL revoked MSN-induced resensitization to anti-PD-1 therapy . Chandra and colleagues prepared manganese (Mn 4+ )-doped silica nanoparticles (Mn 4+ -SNP) with a large pore size to incorporate the viral neoantigen peptide GF001 obtained from HPV16 E7 oncoprotein.…”