Can local radiotherapy and IL-12 synergise to overcome the immunosuppressive tumor microenvironment and allow “in situ tumor vaccination”?

Abstract

Abbreviations ATP Adenosine triphosphate CRT Calreticulin CTLA4 Cytotoxic-T lymphocyte-associated antigen 4 CXCL10/IP-10 Interferon-inducible protein 10 CXCL9/Mig Monokine induced by interferon gamma DAMPs Damage-associated molecular patterns DCs Dendritic cells ESCC Esophageal squamous cell carcinoma GB Glioblastoma HMGB1 High mobility group protein B1 ICD Immunogenic cell death iNOS/M1 Macrophage M1 inducible nitric oxide synthase MDCSs Myeloid-derived suppressor cells NSCLC Non-small cell lung cancer PD1 Programmed cell death protein 1 RT Radiotherapy TGF-β Transforming growth factor-β TH1 Type I T helper TILs Tumor-infiltrating lymphocytes TLR4 Toll like receptor 4 Treg Regulatory T cell(s) The immunogenic tumor cell death and immune modulation induced by radiotherapy Until recently, it had been accepted that the effectiveness of radiation therapy (RT) depends on the "quantity" of RTinduced tumor cell death. Other reports have highlighted the possibility that apoptosis in tumor cells may act as a driver of oncogenic progression especially by promoting angiogenesis and replacement of the dying cells, as well

A Genomic Profile of Local Immunity in the Melanoma Microenvironment Following Treatment with α Particle-Emitting Ultrasmall Silica Nanoparticles

“…The direct pharmacological consequences of a particle irradiation and the silica nanoparticle contribute to tumor killing and TME remodeling. Dynamic changes in macrophage, T cell, and NK cell populations were observed over a 4-5 d period and suggest that ancillary immunotherapeutic approaches [41][42][43][44][45][46] be deployed in combination with the 225 Ac-labeled C¢ dot agents. RNA-seq was used to identify specific immune cell signatures in the TME that occur 4 d after treatment.…”

“…48 The C¢ dot component of the drug undoubtedly prompts inflammatory changes in the TME, which is an active area of ongoing investigation looking to introduce an immunotherapeutic approach to eradicating residual disease. [41][42][43][44][45][46] Importantly, the C¢ dots are a synthetic nanoscale particle and not a live pathogen, therefore, this initial phenotype response has a finite lifetime in vivo and is not a self-sustaining event. We expect that the observed increase in TME Tregs dampens the tumoricidal immunologic activity, therefore, a goal moving forward is to uncover a means to maintain the initial antitumor immune response that we observe.…”

Generating the Abscopal Effect by Combining Proapoptotic Peptides With IL-12-Based Immunotherapy

“…The reproduction of such systemic reaction requires at least two major steps, as described in our published model [6] . First, inducing apoptosis of tumor cells and second, reprogramming the TME into a TH1 polarized response through an IL-12-based immunotherapy.…”

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Figure 1 The intratumor co-administration of IL-12 and proapoptotic peptides (PAPs) generates abscopal effect that reduces massively the contralateral tumor volume (A) and extends the lifespan (B) of BALB/c mice bearing CT26 colon cancer cells. Untreated CT26 tumors (seeded with 3 × 10 5 cells) were established in 6-wk.-old female BALB/c mice, as described previously [6] , [9] . The different treatments were initiated when tumor reach a volume~ 0.3cm 3 .

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“…The different treatments were initiated when tumor reach a volume~ 0.3cm 3 . Only tumor on one side was co-injected with mouse recombinant IL-12 (R&D systems) (delivered at 10 μg/day for a period of 7 days) in the presence or absence of 300 μg (30 μl final) of PAPs (PTD/KLAK) [6] for a period of 7 days only. After that, the contralateral tumor (non-treated side) volume were evaluated twice weekly using a caliper.…”