A single local delivery of paclitaxel and nucleic acids via an immunoactive polymer eliminates tumors and induces antitumor immunity

PD-1 Blockade Enhances Radiation Therapy-Induced Abscopal Effect

Background: Cryoablation of breast cancer (BC) is an out-patient procedure, less invasive than surgery, cost-efficient and may provide the added benefit of anti-tumor immunity. Cryoablation has been approved for small (≤1.5 cm) low-risk (hormone receptor positive) breast tumors and is currently being investigated for high-risk breast cancers (HER2+ and TNBC). Cryoablation uses ultrasound to guide a cryo-probe into the tumor and, through a series of freeze thaw cycles, kills the tumor and induces necrosis. The tumor remains in the patient and renders it “hot” promoting immune cell infiltration while preserving tumor associated antigens (TAA) to generate an immunogenic response. Our pre-clinical reports show cryoablation results in lower rates of tumor recurrence and metastasis with increased TILs at distant tumors. Using a murine model for TNBC cryoablation, we evaluated the immune response following cryoablation compared to surgical resection to identify early mechanism of the abscopal effect and potential biomarkers for cryoablation efficacy. Methods: We used a syngeneic TNBC mouse model with an intact immune system to better understand cryoablation and the abscopal effect utilizing a distant tumor for immune response read out. BALB/c mice were orthotopically transplanted with 1x106 cells of the highly metastatic TNBC 4T1-12b-luciferase expressing cell line into the fourth and ninth mammary fat pad on left and right sides. Tumor growth and metastasis were monitored by palpation, caliper measurements and the in vivo imaging system (IVIS) for luminescence during the course of the experiments. At 2 weeks post-transplantation, the left tumor was treated by either resection or cryoablation. IVIS imaging showed complete tumor cryoablation at 24-hrs. One-week later the mice were sacrificed, necropsied for metastasis and tissues evaluated by flow cytometry for the anti-tumor immune response. Results: The cryoablated tumor had significant infiltration of immune cells (naïve CD4+ T cells and myeloid cells) for tissue damage control and clean-up which allows for de novo TAA presentation. In addition, there was a significant increase in migratory cDC1s (CD103+/XCR1+) in the tumor draining lymph node (TDLN) as well as the spleen (secondary lymphoid tissue). In examining the distant abscopal tumors, cryoablation of the primary tumor resulted in significantly smaller abscopal tumors and changes in TIME with increased activated CD8+ ICOS+ T cells compared to resection. Differentially expressed gene analysis of bulk tumors (cryoablation abscopal vs. resection abscopal) showed increased anti-tumor changes with upregulation of tumor suppressor genes (Stat6 and Nlrp12) and T and NK cell cytotoxicity (Prf1 – perforin) and downregulation of metastatic (Cx3cr1) and angiogenesis and immunosuppression (Cxcl2) genes. STRING analysis for gene pathway ontology showed several immune processes to be involved including immune system process, cell activation, cytokine production, and cell surface receptor signaling pathways. GSEA (gene set enrichment analysis) plot analysis identified significant changes for hallmark genes in the Inflammatory response, IL2-Stat5 Signaling, and IL6-Jak-Stat3 signaling. Conclusion: Our results suggest that cryoablation enhances the myeloid response playing an early role in generating the anti-tumor immune response and potentially influences the TIME at distant tumors. We found increased infiltration of migratory cDC1 (CD103+/XCR1+), potent antigen presenting cells (APC) critical for effective anti-tumor CD8+ T cell priming, in the cryoablated TDLN and spleen. This dendritic cell population also has the ability to “cross-dress”/pass antigens to other APCs, making cDC1s a potential target for immune modulation to increase anti-tumor immunity enhancing the abscopal effect. Citation Format: Flavia Sardela de Miranda, Dalia Martinez-Marin, Rachel L. Babcock, Geetha Pryia Boligala, Nicholas Wagner, Elizabeth Jeffery, Rebecca Joseph, Omar Barakat, Reshad S. Ghafouri, Maria F. Mahecha, Karla Daniele, Kevin Pruitt, Sharda P. Singh, Michael W. Melkus, Rakhshanda Layeequr Rahman. Tumor Immune Micro-Environment (TIME) Effect of Cryoablation in Triple-Negative Breast Cancer - It was the best of TIMES [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-06-16.

Background: Immune checkpoint inhibitors (ICIs), such as anti-CTLA-4 which acts primarily during T cell priming and anti-PD-1 which targets exhausted T cells, have shown clinical efficacy in triple-negative breast cancer (TNBC) but are associated with immune-related adverse events. These limitations underscore the need for combination strategies that enhance therapeutic outcomes and reduce ICI dosing requirements. Cryoablation, a non-surgical procedure, “kills” the tumor through freeze-thaw cycles while preserving tumor-associated antigens (TAAs). This procedure induces tumor necrosis and release of damage-associated molecular patterns that trigger antitumor immune responses and may enhance the abscopal effect - systemic immune response against distant tumors. The immune activation is mediated by immune cells recruited to the ablation site and tumor-draining lymph nodes (TdLNs). Conventional dendritic cells (cDC) play a central role in antitumor immunity by capturing TAAs and presenting them to T cells. Among cDC subsets, cDC1 - including lymphoid resident (CD8α+) and migratory (CD103+) populations - specialize in cross-presenting antigens to CD8+ T cells, while cDC2 primarily present antigens to CD4+ T cells. We hypothesized that combining cryoablation with ICIs enhances antitumor immunity by promoting antigen presentation and T cell activation. Methods: In a murine TNBC cryoablation model, 4T1-12B cells were bilaterally injected into BALB/c mice. The left (primary) tumors were cryoablated at 2 weeks, while the right tumors (abscopal tumors) were left intact to represent distant metastatic tumors to examine the immune abscopal effect. PBS or 100 µg ICI (anti-CTLA-4, PD-1, or PD-L1) were administered by I.P. injection 24h pre- and post-cryoablation. Mice were sacrificed a week later and evaluated for early immune activation. The primary and abscopal tumors and TdLNs, peripheral blood, and spleen were collected, processed and analyzed for immune system activation by flow cytometry. Results: Preliminary analyses demonstrated that combining cryoablation with anti-CTLA-4 therapy enhanced CD4+ and CD8+ T cell activation in both the spleen and peripheral blood compared to cryoablation alone or in combination with PD-1/PD-L1 blockade. Notably, relative to cryoablation monotherapy, the addition of anti-CTLA-4 increased the frequency and activation of both cDC1 and cDC2 subsets in the abscopal TdLNs. Among cDC1 populations, the lymphoid resident subset was significantly elevated in the cryoablation plus anti-CTLA-4 group. Furthermore, abscopal tumors from this group showed a higher frequency of activated CD4+ and CD8+ T cells, as well as NKT cells. Conclusions: These results suggest combination of cryoablation with anti-CTLA-4 therapy enhances systemic antitumor immunity more effectively than cryoablation alone or with PD-1/PD-L1 inhibition. One possible explanation is that cryoablation destroys the entire tumor immune microenvironment, resulting in fewer effector T cells for PD-1/PD-L1 inhibitors to act upon, which limits efficacy in this context. In contrast, anti-CTLA-4 may act earlier in the immune response by promoting de novo T cell priming. We observed increased frequencies and activation of cDC1 and cDC2 in the TdLNs of abscopal tumors, which likely contributed to the elevated numbers of activated CD4+ and CD8+ T cells in the abscopal tumor microenvironment. Altogether, these findings highlight the potential of cryoablation combined with anti-CTLA-4 to enhance antitumor immunity. Our results support further investigation into this combination strategy to assess its long-term potential to prevent tumor recurrence and metastasis. Citation Format: F. Sardela de Miranda, R. L. Babcock, G. P. Boligala, M. F. Mahecha, P. J. Gukhool, A. K. Garcia, A. G. Oliver, C. Bose, S. Almodovar, K. Pruitt, S. P. Singh, M. W. Melkus, R. Layeequr Rahman. Cryoablation Combined with Immune Checkpoint Inhibitors Enhances Conventional Dendritic Cell Activation in Abscopal Tumors and Tumor-Draining Lymph Nodes [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-13-13.

BackgroundAn immunoactive complex consisting of a polyethyleneimine derivative (2E’), cytotoxic drug, and nucleotide is developed to stimulate innate immune cells in solid tumors. Each component has unique roles: 2E’ induces...

Immune checkpoint blockade (ICB) is a powerful oncologic treatment modality for a wide variety of human malignancies, but the patient response rate to this treatment remains low, especially in patients with cutaneous squamous cell carcinoma (cSCC). 5-Aminoleuvulinic acid-photodynamic therapy (ALA-PDT) is widely used to treat cancerous and precancerous skin diseases, but the value of ALA-PDT in the treatment of invasive cSCC is debatable. Our previous studies have shown that ALA-PDT can induce antitumor immune responses by promoting the immunogenic death of tumor cells. However, it is unclear whether ALA-PDT exerts synergistic effects with ICB in cSCC. Here, we report that PD-L1 blockade potentiates the antitumor effects of ALA-PDT both on primary and distant tumors, and optimizes the tumor microenvironment in cSCC. In this study, we first detected PD-L1 expression in patients with different grades of cSCC. Then we found the combination of anti-PD-L1 monoclonal antibody (mAb) and ALA-PDT killed tumor cells by apoptosis- and/or ferroptosis-mediated immunogenic cell death (ICD) and stimulated systemic immune response, as well as building the immunological memory response to prevent tumor recurrence. Furthermore, we found that combination therapy can be used to recruit tertiary lymphoid structure (TLS)-like intratumoral lymphoid aggregates, which may promote tumor-infiltrating lymphocyte (TIL)-mediated antitumor immunity. In summary, our work demonstrates that ICB treatment with an anti-PD-L1 antibody is a promising strategy that may potentiate the antitumor effects of ALA-PDT in cSCC.

BackgroundDespite its potential utility in delivering direct tumor killing and in situ whole-cell tumor vaccination, tumor cryoablation produces highly variable and unpredictable clinical response, limiting its clinical utility. The mechanism(s)...

SY39-02: Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity

Preclinical and clinical studies have shown that intratumoral oncolytic viruses (OVs) can convert “cold” tumors to “hot” and overcome resistance to immune checkpoint blockade. However, their modest clinical efficacy to date highlights major gaps in our understanding of how OVs interact with the immune system, and very limited information is available regarding the specificity of the T cell repertoires that emerge within tumors in response to OV therapy. To address these gaps, we interrogated the evolution of immune response to OV therapy in mice using oncolytic Newcastle Disease Virus (NDV). Leveraging a bilateral flank melanoma mouse model, we identified and phenotypically characterized anti-viral and anti-tumor T cells in local and abscopal tumors with single cell (sc) RNA and T cell receptor (TCR) sequencing. Intratumoral NDV therapy to a single flank tumor resulted in increased infiltration of CD4+ and CD8+ T cells in both the injected and distant tumors, higher TCR overlap between treated and distant tumors, and higher frequency of convergent TCR clonotypes, suggesting their non-random expansion, albeit without specificity information. To identify the specificity of the emergent TCR clones in an unbiased fashion, we developed an approach based on adoptive transfer of T cells from tumor-bearing control or NDV-treated donor mice into congenically marked recipients with either B16 or NDV antigen stimulation. This allowed the isolation and identification of expanded B16- or virus-specific TCR clones that were then linked to donor tumors to define their relative frequencies, their distribution across the treated and distant tumors, and their associated phenotypic states. We observed significantly greater expansion of B16-reactive T cells adoptively transferred from NDV-treated donors (compared to control donors), suggesting that NDV therapy leads to potentiation of tumor-specific immune response. Intriguingly, virus-specific and tumor-specific T cells appeared to distribute to distinct phenotypic clusters, with virus-specific and tumor-specific T cells found predominantly in the activated-dysfunctional and proliferating clusters, respectively. When looking at the distribution of the TCR clones, virus-specific clones dominated the majority of the response in both treated and distant tumors, despite the lack of virus injection in distant tumors. These results provide insights into understanding the balance between virus- and tumor-directed immune responses elicited by OV therapy and highlight that even in the presence of significant abscopal immune effect, the significant proportion of T cells in “hot” tumors represent anti-viral rather than anti-tumor response. These findings provide tools for tracking of immune response specificity and generate rationale for development of OV engineering strategies and combinations that favor anti-tumor rather than anti-viral immunity. Citation Format: Olga Lyudovyk, Bharat Burman, Nicholas Ceglia, Benjamin Greenbaum, Yuval Elhanati, Dmitriy Zamarin. Evolution of anti-viral and anti-tumor immunity in tumors in response to oncolytic virus therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB400.

Background: The stimulator of interferon genes (STING) plays a central role in innate immune response against infection and cancer. Several cyclic di-nucleotide (CDN) and non-CDN small molecule STING agonists have demonstrated effectiveness against cancer in preclinical animal models, however their clinical trials showed limited therapeutic efficacy. ONM-501, a dual-activating STING agonist employs PC7A, a synthetic polymer that induces polyvalent STING condensation and prolongs innate immune activation has been recently developed. ONM-501 encapsulates the endogenous STING agonist cGAMP with the PC7A micelles offering dual ‘burst’ and ‘sustained’ STING activation. The mechanism and effectiveness of intratumorally delivered ONM-501 as an immunotherapy against solid tumors has been demonstrated in preclinical models. Methods: ONM-501 was recently evaluated for STING activation across different species: STING related IFNB1 and CXCL10 gene expression after ONM-501 treatment was measured by RT-qPCR in PBMCs from rat, cynomolgus monkey, and human. ONM-501 antitumor efficacy was evaluated in murine syngeneic tumor models. Abscopal effect was demonstrated by studying antitumor efficacy using both a primary/distal model and a lung metastatic model. STING knockout mice and STING knockout cancer cells were used to clarify the dependence of STING status to the ONM-501 antitumor immunity. Immune cell dependence was further elucidated by depletion of specific immune cell populations. Pilot safety studies including major organ function and systemic cytokine levels were performed in immunocompetent mice. Results: STING activation was observed across different species by measuring IFNB1 and CXCL10 mRNA in PBMCs from rat, cynomolgus monkey, and human after ONM-501 treatment. Antitumor efficacy was demonstrated both as a monotherapy and in combination with anti-PD1 in six different syngeneic tumor models. ONM-501 also induced an abscopal effect - tumor inhibition was observed in both primary and distal MC38 tumors in the same animal. Reduction of lung metastasis in an immune “cold” triple negative orthotopic breast cancer 4T1 model further confirmed the systemic antitumor immunity. Knocking out host STING (i.e. STING KO mice) rather than cancer cell STING KO resulted in abrogation of tumor inhibition suggesting that the host STING status is responsible for ONM-501-mediated anti-tumor immunity. Immune cell depletion studies further clarified that the antitumor immunity is dependent on CD8+ T cell and dendritic cells (DCs). No alteration of main organ function or systemic cytokine storm were observed in the pilot safety study. Conclusions: ONM-501 demonstrated marked anti-tumor efficacy in a panel of syngeneic tumor models. The anti-tumor effect was mediated by host STING and dependent on CD8+ T cells and DCs. These results support further evaluation of ONM-501 as a clinical candidate for the potential treatment of solid tumors. Citation Format: Suxin Li, Jian Wang, Jonathan Wilhelm, Qingtai Su, Gaurav Bharadwaj, Jason Miller, Wei Li, Katy Torres, Ruolan Han, Tian Zhao, Jinming Gao. ONM-501: A polyvalent STING agonist for oncology immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4234.

TIGIT (T cell immunoreceptor with Ig ITIM domain) is a co-inhibitory receptor and its signaling axis inhibits T cell and Natural Killer (NK) cell activity in the healthy immune system. In tumors TIGIT is highly expressed on a subset of dysfunctional T and NK cells and of highly suppressive regulatory T cells (Treg). Loss of TIGIT signaling enhances NK cell activity, CD4+ T cell priming and CD8+ T cell effector functions, suggesting a role in anti-tumor immunity. We have developed an anti-TIGIT blocking antibody that shows potent antitumor efficacy in in multiple syngeneic mouse models, including CT26WT colon, B16F10 melanoma and 4T1 breast cancer. Dose-dependent (12.5-0.1 mg/Kg) single agent efficacy was demonstrated in established tumors, and pharmacodynamic (PD) biomarkers in blood and in tumors were identified. Consistent with TIGIT’s role as a co-inhibitory receptor, anti-TIGIT promoted a dose-dependent increase in activation of CD8+ and CD4+ tumor infiltrating leukocytes (TIL) and NK cells, as shown by increased staining of IFN-γ and CD69 by flow cytometry, when compared to controls. Anti-TIGIT also increased CD4 and CD8 T cell frequency in the tumor, measured by immunohistochemistry (IHC). Furthermore, anti-TIGIT caused an increase in splenic NK cell cytotoxicity, which correlated with dose and efficacy. To identify gene expression biomarkers in tumor and in blood, we used microarray analysis, and found similar immune gene changes between the two tissues. As expected, anti-TIGIT increased the expression of genes associated with CD8+ T cells, CD4+ T cells, and NK cells. Markers indicative of cytotoxic activity and Th1 response were also induced by anti-TIGIT. The microarray data were validated by qRT-PCR and results were consistent with flow cytometry and cytotoxicity results, and underlie the mechanism of action of anti-TIGIT. We have developed an IHC assay to evaluate TIGIT expression patterns in tumor and the associated stroma and TILs. Using this assay, we profiled 17 tumor types to evaluate patterns of TIGIT expression. Expression was high on immune cells in the stroma and on TILs in 8 tumor types, while it was generally low on tumor cells. TIGIT expression was also low on tumor cells in a panel of 27 PDX models. Consistent with the IHC results, analysis of 33 tumor types in the TCGA by RNA-Seq showed a good correlation of the expression levels of TIGIT and T cell markers, suggesting that TIGIT is mostly expressed on immune cells in tumors. In conclusion, we have identified PD biomarkers for anti-TIGIT in tumors and in surrogate tissues in syngeneic mouse models. Analysis of the biomarkers demonstrates activation of T cells and NK cells upon inhibition of TIGIT signaling. These biomarkers can be used in the clinic to demonstrate target engagement. In addition, we have profiled the expression of TIGIT in multiple solid tumor types and characterized prevalence of TIGIT-positive cells. Citation Format: Fiore Cattaruzza, Pete Yeung, Min Wang, Alayne Brunner, Erwan Le Scolan, Jennifer Cain, Gretechen Argast, Gilbert O'Young, YuWang Liu, Belinda Cancilla, Austin Gurney, Tim Hoey, John Lewicki, Ann Kapoun. Pharmacodynamic biomarkers for anti-TIGIT treatment and prevalence of TIGIT expression in multiple solid tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 599. doi:10.1158/1538-7445.AM2017-599

Apart from the cytotoxic effect of radiation- or chemotherapy it has become evident that these treatments are able to induce an immune response which can play an additional and pivotal role in clearing tumours. This treatment-induced immunogenic tumour cell death (ICD) enables the host's immune system to recruit to the tumour and recognise and kill tumour cells which can even extend to yet untreated metastases, a phenomenon called “abscopal effect”. For the first time, we found evidence that radiation and/or chemo-treatment stimulates a pronounced up-regulation of both, PD-L1 and Galectin-9 on pre-apoptotic and apoptotic gastric tumour cells. Both these proteins exert immuno-modulatory signals which in turn may dampen the aimed immunogenicity of the treatment. PD-L1, which is the ligand to programmed cell death protein 1 (PD1) on T cells, and its upregulation is commonly used by cancer cells to evade immunity. PD-L1 causes T cell apoptosis and hence an inhibition of T cell driven anti-tumour immunity. Galectin-9 exerts immunoinhibitory functions and is, together with the immunostimulatory molecule HMGB1, a competitive binding partner for the receptor T-cell immunoglobulin domain and mucin domain 3 (Tim-3). Once engaged by its ligand, Tim-3 either exerts stimulatory or inhibitory effects, depending on ligand, cell type, maturation state and Tim-3 expression rate. Together with PD-L1, Galectin-9 enables a complex interplay between cancer cells and cells of the adaptive immune response expressing PD1 and Tim-3. Based on these results, we are investigating the mechanism responsible for PD-L1 and Galectin-9 upregulation and the effect on the efficacy of radio- as well as chemotherapy on tumour eradication. Additionally, due to their potentially enhancing effect on anti-tumour immunity, we are studying the therapeutic value of blocking Abs specific for human PD1 and/or Tim-3 in cancer immunotherapy. Citation Format: Sven H. Petersen. Radio- and chemotherapy causes up-regulation of immunoinhibitory ligands pd-l1 and galectin-9 in gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 547.

Background Low-dose radiotherapy (RT) is a promising treatment likely to increase the efficacy of immunotherapy, including programmed cell death ligand 1 (PD-L1) blockade, in cancer therapy. Further exploration and optimization of such combinatorial strategies are required. Notably, the ability of low-dose RT to enhance the efficacy of immune-checkpoint inhibitors (ICI) in distant, unirradiated tumors is debated. Methods We used a stepwise preclinical approach in immunocompetent mice bearing different murine tumor models (MC38 or CT26), with one or two tumors per mouse. Mice received tumor-only irradiation consisting of either low-dose RT (2x0.5 Gy to 2x2 Gy) or high-dose RT (2x6 Gy to 2x8 Gy) combined with anti-PD-L1. Tumor growth rate and survival were compared across the different conditions. The immune microenvironments of both irradiated and distant unirradiated tumors were characterized using single-cell RNA sequencing. Results We first demonstrated that low-dose RT 2×2 Gy combined with anti-PD-L1 is as effective as high-dose RT 2×6 Gy in delaying the growth of irradiated tumors. Subsequently, we showed that low-dose RT to one tumor enhances the efficacy of anti-PD-L1 consolidation therapy in a distant, unirradiated tumor, thereby inducing an abscopal effect comparable to that observed with high-dose RT. Single-cell RNA sequencing analysis highlighted the polarization of tumor-associated macrophages (TAMs) within distant unirradiated tumors towards a pro-inflammatory phenotype following low-dose RT and anti-PD-L1. Depleting TAMs in distant unirradiated tumors using liposomal clodronate abrogated the abscopal effect driven by low-dose RT combined with anti-PD-L1. Conclusion Our findings demonstrate the ability of low-dose RT to increase the efficacy of ICI in a distant tumor, resulting in a significant abscopal effect, and highlight the critical role of TAMs in the underlying mechanism, as well as a potential immune crosstalk between TAMs and activated lymphoid cells. These data propose low-dose RT as a potential strategy to improve the efficacy of immunotherapy in patients with metastatic solid tumors receiving anti-PD-L1.

Breast cancer is the most diagnosed cancer and the second leading cause of cancer death in women. Although treatments with major anti-cancer modalities are largely successful, resistance to treatments including widely applied radiation therapy (RT) can occur due largely to the multifaceted mechanisms in the tumor microenvironment (TME). The present work investigated the ability of Polymer-Lipid-Manganese Dioxide Nanoparticles (PLMD) to overcome hypoxia-associated radioresistant mechanisms and enhance RT-induced immunogenic cell death (ICD) and anti-tumor immunity for inhibiting growth of primary and distant tumors (the abscopal effect). The results showed that PLMD plus RT significantly inhibited the clonogenic survival of murine EMT6 and 4T1 breast cancer cells under hypoxic condition compared to RT alone. Analysis of ICD biomarkers revealed that PLMD profoundly enhanced RT-induced ICD compared to RT alone in EMT6 and 4T1 cells under hypoxic conditions but not under normoxic conditions. In a syngeneic murine breast tumor model with 4T1 orthotopic tumor, the PLMD treatment reduced tumor hypoxia significantly; PLMD + RT combination therapy increased infiltration of cytotoxic CD8+ T cells and CD86+ macrophages and decreased infiltration of immunosuppressive Tregs and CD163+ macrophages, as compared to RT alone. Importantly, the PLMD + RT treatment generated an abscopal effect in a tumor growth experiment using a double-tumor model, where the growth of an untreated tumor was inhibited by treatment of a tumor grown on the opposite side. Overall, the PLMD + RT induced an anti-tumor immune response that inhibited both primary and distant tumor growths and extended median survival in the tumor model.

Tumor Cell-Intrinsic PD-L1 Effects on Radiation-Induced Locoregional Antitumor Immunity

BackgroundToll-like receptors (TLRs) are critical innate immune sensors that elicit antitumor immune responses in cancer immunotherapy. Although a few TLR agonists have been approved for the treatment of patients with...