TripHLApan: predicting HLA molecules binding peptides based on triple coding matrix and transfer learning.

Human leukocyte antigen (HLA) recognizes foreign threats and triggers immune responses by presenting peptides to T cells. Computationally modeling the binding patterns between peptide and HLA is very important for the development of tumor vaccines. However, it is still a big challenge to accurately predict HLA molecules binding peptides. In this paper, we develop a new model TripHLApan for predicting HLA molecules binding peptides by integrating triple coding matrix, BiGRU + Attention models, and transfer learning strategy. We have found the main interaction site regions between HLA molecules and peptides, as well as the correlation between HLA encoding and binding motifs. Based on the discovery, we make the preprocessing and coding closer to the natural biological process. Besides, due to the input being based on multiple types of features and the attention module focused on the BiGRU hidden layer, TripHLApan has learned more sequence level binding information. The application of transfer learning strategies ensures the accuracy of prediction results under special lengths (peptides in length 8) and model scalability with the data explosion. Compared with the current optimal models, TripHLApan exhibits strong predictive performance in various prediction environments with different positive and negative sample ratios. In addition, we validate the superiority and scalability of TripHLApan's predictive performance using additional latest data sets, ablation experiments and binding reconstitution ability in the samples of a melanoma patient. The results show that TripHLApan is a powerful tool for predicting the binding of HLA-I and HLA-II molecular peptides for the synthesis of tumor vaccines. TripHLApan is publicly available at https://github.com/CSUBioGroup/TripHLApan.git.

Programming of in Situ Tumor Vaccines via Supramolecular Nanodrug/Hydrogel Composite and Deformable Nanoadjuvant for Cancer Immunotherapy.

The development of in situ tumor vaccines offers promising prospects for cancer treatment. Nonetheless, the generation of plenary autologous antigens in vivo and their codelivery to DC cells along with adjuvants remains a significant challenge. Herein, we developed an in situ tumor vaccine using a supramolecular nanoparticle/hydrogel composite (ANPMTO/ALCD) and a deformable nanoadjuvant (PPER848). The ANPMTO/ALCD composite consisted of ß-cyclodextrin-decorated alginate (Alg-g-CD) and MTO-encapsulated adamantane-decorated nanoparticles (ANPMTO) through supramolecular interaction, facilitating the long-term and sustained production of plenary autologous antigens, particularly under a 660 nm laser. Simultaneously, the produced autologous antigens were effectively captured by nanoadjuvant PPER848 and subsequently transported to lymph nodes and DC cells, benefiting from its optimized size and deformability. This in situ tumor vaccine can trigger a robust antitumor immune response and demonstrate significant therapeutic efficacy in inhibiting tumor growth, suppressing tumor metastasis, and preventing postoperative recurrence, offering a straightforward approach to programming in situ tumor vaccines.

IL-2 promotes expansion and intratumoral accumulation of tumor infiltrating dendritic cells in pancreatic cancer.

This study aims to investigate the diagnostic potential of IL-2 for PDAC and develop a method to improve the dendritic cell (DC) based vaccine against PDAC. The gene expression data and clinical characteristics information for 178 patients with PDAC were obtained from The Cancer Genome Atlas (TCGA). DCs were isolated from Human peripheral blood mononuclear cells (PBMCs) and were cultured in 4 different conditions. DCs were pulsed by tumor cell lysates or KRAS G12D1 - 23 peptide, and then used to activate T cells. The mixture of DCs and T cells were administered to xenograft mouse model through the tail vein. The infiltration of DCs and T cells were detected by immunohistochemistry. The generation of KRAS G12D mutation specific cytotoxic T cells was determined by in vitro killing assay. We observed that PDAC patients with higher IL-2 mRNA levels exhibited improved overall survival and increased infiltration of CD8 + T cells, NK cells, naïve B cells, and resting myeloid DCs in the tumor microenvironment. IL-2 alone did not enhance DC proliferation, antigen uptake, or apoptosis inhibition unless co-cultured with PBMCs. DCs co-cultured with PBMCs in IL-2-containing medium demonstrated the strongest tumor repression effect in vitro and in vivo. Compared to DCs obtained through the traditional method (cultured in medium containing GM-CSF and IL-4), DCs cultured with PBMCs, and IL-2 exhibited increased tumor infiltration capacity, potentially facilitating sustained T cell immunity. DCs cultured in the PBMCs-IL-2 condition could promote the generation of cytotoxic T cells targeting tumor cells carrying KRAS G12D mutation.

Photodynamic Therapy Derived Personalized Whole Cell Tumor Vaccine Prevents Postsurgery Tumor Recurrence and Metastasis.

In order to avoid the time-consuming and laborious identification of tumor-specific antigens (TSAs) during the traditional vaccine fabrication process, a versatile photodynamic therapy (PDT)-based method is developed to construct a whole-tumor antigen tumor vaccine (TV) from surgically resected tumor tissues for personalized immunotherapy. Mucoadhesive nanoparticles containing small-molecular photosensitizer are fabricated and directly co-incubated with suspended tumor cells obtained after cytoreduction surgery. After irradiation with a 405 nm laser, potent immunogenic cell death of cancer cells could be induced. Along with the release of TSAs, the as-prepared TV could activate safe and robust tumor-specific immune responses, leading to efficient suppression of postsurgery tumor recurrence and metastasis. The as-prepared TV cannot only be applied alone through various administration routes but also synergize with immunoadjuvant, chemotherapeutics, and immune checkpoint blockers to exert more potent immune responses. This work provides an alternative way to promote the clinical translation of PDT, which is generally restricted by the limited penetration of light. Moreover, the versatile strategy of vaccine fabrication also facilitates the clinical application of personalized whole-cell tumor vaccines.

Preimmunization with Listeria-vectored cervical cancer vaccine candidate strains can establish specific T-cell immune memory and prevent tumorigenesis.

BACKGROUND: Although HPV prophylactic vaccines can provide effective immune protection against high-risk HPV infection, studies have shown that the protective effect provided by them would decrease with the increased age of vaccination, and they are not recommended for those who are not in the appropriate age range for vaccination. Therefore, in those people who are not suitable for HPV prophylactic vaccines, it is worth considering establishing memory T-cell immunity to provide long-term immune surveillance and generate a rapid response against lesional cells to prevent tumorigenesis. METHODS: In this study, healthy mice were preimmunized with LM∆E6E7 and LI∆E6E7, the two Listeria-vectored cervical cancer vaccine candidate strains constructed previously by our laboratory, and then inoculated with tumor cells 40 d later. RESULTS: The results showed that preimmunization with LM∆E6E7 and LI∆E6E7 could establish protective memory T-cell immunity against tumor antigens in mice, which effectively eliminate tumor cells. 60% of mice preimmunized with vaccines did not develop tumors, and for the remaining mice, tumor growth was significantly inhibited. We found that preimmunization with vaccines may exert antitumor effects by promoting the enrichment of T cells at tumor site to exert specific immune responses, as well as inhibiting intratumoral angiogenesis and cell proliferation. CONCLUSION: Altogether, this study suggests that preimmunization with LM∆E6E7 and LI∆E6E7 can establish memory T-cell immunity against tumor antigens in vivo, which provides a viable plan for preventing tumorigenesis and inhibiting tumor progression.

Cancer immunotherapy of Wilms tumor: a narrative review.

Wilms tumor (WT) is the most common malignant tumor of the urinary system in children. Though the traditional treatment of surgery plus radiotherapy and chemotherapy achieves exciting clinical efficacy, in relapsed and refractory cases, the long-term overall survival rates are poor. Besides, chemotherapy and radiation have serious long-term toxic side effects on children. Cancer immunotherapy is a new tumor therapy that works by activating the body's immune system to allow immune cells to kill tumor cells more efficiently. Currently, cancer immunotherapy has been tested in clinical trials or basic studies in WT. This article reviews the current status of clinical trials and basic research of cancer immunotherapy in WT to promote the application of cancer immunotherapy in WT patients.

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Recent advances and future challenges of tumor vaccination therapy for recurrent glioblastoma.

Glioblastoma (GBM) is the most malignant CNS tumor with a highest incidence rate, and most patients would undergo a recurrence. Recurrent GBM (rGBM) shows an increasing resistance to chemotherapy and radiotherapy, leading to a significantly poorer prognosis and the urgent need for novel treatments. Immunotherapy, a rapidly developing anti-tumor therapy in recent years, has shown its potential value in rGBM. Recent studies on PD-1 immunotherapy and CAR-T therapy have shown some efficacy, but the outcome was not as expected. Tumor vaccination is the oldest approach of immunotherapies, which has returned to the research focus because of the failure of other strategies and subversive understanding of CNS. The isolation effect of blood brain barrier and the immunosuppressive cell infiltration could lead to resistance existing in all phases of the anti-tumor immune response, where novel tumor vaccines have been designed to overcome these problems through new tumor antigenic targets and regulatory of the systematic immune response. In this review, the immunological characteristics of CNS and GBM would be discussed and summarized, as well as the mechanism of each novel tumor vaccine for rGBM. And through the review of completed early-phase studies and ongoing large-scale phase III clinical trials, evaluation could be conducted for potential immune response, biosecurity and initial clinical outcome, which further draw a panorama of this vital research field and provide some deep thoughts for the prospective tendency of vaccination strategy. Video Abstract.

Exploiting immunostimulatory mechanisms of immunogenic cell death to develop membrane-encapsulated nanoparticles as a potent tumor vaccine.

Vaccine is one of the most promising strategies for cancer immunotherapy; however, there are no therapeutic cancer vaccine achieving significant clinical efficacy till now. The main limiting factors include the immune suppression and escape mechanisms developed by tumor and not enough capacity of vaccines to induce a vigorous anti-tumor immunity. This study aimed to develop a strategy of membrane-based biomimetic nanovaccine and investigate the immunological outcomes of utilizing the unique immunostimulatory mechanisms derived of immunogenic cell death (ICD) and of fulfilling a simultaneous nanoscale delivery of a highlighted tumor antigen and broad membrane-associated tumor antigens in the vaccine design. TC-1 tumor cells were treated in vitro with a mixture of mitoxantrone and curcumin for ICD induction, and then chitosan (CS)-coated polylactic co-glycolic acid (PLGA) nanoparticles loaded with HPV16 E744-62 peptides were decorated with the prepared ICD tumor cell membrane (IM); further, the IM-decorated nanoparticles along with adenosine triphosphate (ATP) were embedded with sodium alginate (ALG) hydrogel, And then, the immunological features and therapeutic potency were evaluated in vitro and in vivo. The nanovaccine significantly stimulated the migration, antigen uptake, and maturation of DCs in vitro, improved antigen lysosome escape, and promoted the retention at injection site and accumulation in LNs of the tumor antigen in vivo. In a subcutaneously grafted TC-1 tumor model, the therapeutic immunization of nanovaccine elicited a dramatical antitumor immunity. This study provides a strategy for the development of tumor vaccines.

Cancer Vaccines Based on Fluorine-Modified KH-1 Elicit Robust Immune Response.

KH-1 is a tumor-associated carbohydrate antigen (TACA), which serves as a valuable target of antitumor vaccines for cancer immunotherapies. However, most TACAs are thymus-independent antigens (TD-Ag), and they tend to induce immunological tolerance, leading to their low immunogenicity. To overcome these problems, some fluorinated derivatives of the KH-1 antigen were designed, synthesized, and conjugated to the carrier protein CRM197 to form glycoconjugates, which were used for immunological studies with Freund's adjuvant. The results showed that fluorine-modified N-acyl KH-1 conjugates can induce higher titers of antibodies, especially IgG, which can recognize KH-1-positive cancer cells and can eliminate cancer cells through complement-dependent cytotoxicity (CDC). The trifluoro-modified KH-1-TF-CRM197 showed great potential as an anticancer vaccine candidate.

[Status Quo and Development of Immunotherapy for Hepatocellular Carcinoma].

Liver cancer is a serious global health problem and a common cause of cancer-related death. Hepatocellular carcinoma (HCC) is a common pathological type of liver cancer. The clinical symptoms of early HCC tend to be not obvious and 50% of HCC patients are already in the advanced stage by the time they are diagnosed. Systemic therapy is recommended for the treatment of advanced HCC. With the development of molecular targeted drugs (sorafenib and lenvatinib), some progress has been made in the systemic treatment of advanced HCC, but there is only modest benefit for the survival of HCC patients. In recent years, the emergence of immune checkpoint inhibitors has changed the overall outlook of HCC treatment, providing more possibilities for precise treatment of HCC and showing better treatment outcomes. In particular, the combination therapy of atezolizumab and bevacizumab significantly improved the survival outcomes in HCC patients. In addition, adoptive cell therapy, tumor vaccine, oncolytic viruses, and nonspecific immunotherapy have also emerged as strategies for immunotherapy. Herein, the status quo and development of HCC immunotherapy are reviewed.

Invariant NKT cell-augmented GM-CSF-secreting tumor vaccine is effective in advanced prostate cancer model.

Invariant natural killer T cells (iNKT cells) express a semi-invariant T cell receptor that recognizes certain glycolipids (including α-galactosylceramide, αGC) bound to CD1d, and can induce potent antitumor responses. Here, we assessed whether αGC could enhance the efficacy of a GM-CSF-producing tumor cell vaccine in the transgenic SV40 T antigen-driven TRAMP prostate cancer model. In healthy mice, we initially found that optimal T cell responses were obtained with αGC-pulsed TRAMP-C2 cells secreting GM-CSF and milk fat globule epidermal growth factor protein-8 (MFG-E8) with an RGD to RGE mutation (GM-CSF/RGE TRAMP-C2), combined with systemic low dose IL-12. In a therapeutic model, transgenic TRAMP mice were then castrated at ~ 20 weeks, followed by treatment with the combination vaccine. Untreated mice succumbed to tumor by ~ 40 weeks, but survival was markedly prolonged by vaccine treatment, with most mice surviving past 80 weeks. Prostates in the treated mice were heavily infiltrated with T cells and iNKT cells, which both secreted IFNγ in response to tumor cells. The vaccine was not effective if the αGC, IL-12, or GM-CSF secretion was eliminated. Finally, immunized mice were fully resistant to challenge with TRAMP-C2 cells. Together these findings support further development of therapeutic vaccines that exploit iNKT cell activation.

Whole-cell tumor vaccines desialylated to uncover tumor antigenic Gal/GalNAc epitopes elicit anti-tumor immunity.

BACKGROUND: Aberrant sialoglycans on the surface of tumor cells shield potential tumor antigen epitopes, escape recognition, and suppress activation of immunocytes. α2,3/α2,6Gal- and α2,6GalNAc (Gal/GalNAc)-linked sialic acid residues of sialoglycans could affect macrophage galactose-type lectins (MGL) mediated-antigen uptake and presentation and promote sialic acid-binding immunoglobulin-like lectins (Siglecs) mediated-immunosuppression. Desialylating sialoglycans on tumor cells could present tumor antigens with Gal/GalNAc residues and overcome glyco-immune checkpoints. Thus, we explored whether vaccination with desialylated whole-cell tumor vaccines (DWCTVs) triggers anti-tumor immunity in ovarian cancer (OC). METHODS: Sialic acid (Sia) and Gal/GalNAc residues on OC A2780, OVCAR3, and ID8 cells treated with α2-3 neuraminidase (α2-3NA) and α2-6NA, and Sigec-9 or Siglec-E and MGL on DCs pulsed with desialylated OC cells were identified using flow cytometry (FCM); RT-qPCR determined IFNG expression of T cells, TRBV was sequenced using Sanger sequencing and cytotoxicity of αß T cells was measured with LDH assay; Anti-tumor immunity in vivo was validated via vaccination with desialylated whole-cell ID8 vaccine (ID8 DWCTVs). RESULTS: Gal/GalNAc but not Sia residues were significantly increased in the desialylated OC cells. α2-3NA-modified DWCTV increased MGL but decreased Siglec-9 or Siglec E expression on DCs. MGLbright/Siglec-9dim DCs significantly up-regulated IFNG expression and CD4/CD8 ratio of T cells and diversified the TCR repertoire of αß T-cells that showed enhanced cytotoxic activity. Vaccination with α2-3NA-modified ID8 DWCTVs increased MGLbright/Siglec-Edim DCs in draining lymph nodes, limited tumor growth, and extended survival in tumor-challenged mice. CONCLUSION: Desialylated tumor cell vaccine could promote anti-tumor immunity and provide a strategy for OC immunotherapy in a clinical setting.

Nanosized drug delivery systems modulate the immunosuppressive microenvironment to improve cancer immunotherapy.

Immunotherapy that activates immune systems for combating cancer has yielded considerable clinical benefits recently. However, the immunosuppressive tumor microenvironment (ITME) is a major hurdle to immunotherapy as it supports tumor to evade immune surveillance. Reversing ITME facilitates the recruitment and activation of antitumor immune cells, thereby promoting immunotherapy. Our group has developed various nanosized drug delivery systems (NDDSs) to modulate ITME with enhanced efficacy and safety. In the review we introduce the ITME-remodeling strategies for improving immunotherapy based on NDDSs including triggering tumor cells to undergo immunogenetic cell death (ICD), applying tumor vaccine, and directly regulating intratumoral immune components (immune cells or cytokines). In order to guide the design of NDDSs for amplified effects of antitumor immunotherapy, the contributions and future directions of this field are also discussed.

MF59 Promoted the Combination of CpG ODN1826 and MUC1-MBP Vaccine-Induced Antitumor Activity Involved in the Enhancement of DC Maturation by Prolonging the Local Retention Time of Antigen and Down-Regulating of IL-6/STAT3.

Our previous study found that CpG oligodeoxynucleotides 1826 (CpG 1826), combined with mucin 1 (MUC1)-maltose-binding protein (MBP) (M-M), had certain antitumor activity. However, this combination is less than ideal for tumor suppression (tumors vary in size and vary widely among individuals), with a drawback being that CpG 1826 is unstable. To solve these problems, here, we evaluate MF59/CpG 1826 as a compound adjuvant with M-M vaccine on immune response, tumor suppression and survival. The results showed that MF59 could promote the CpG 1826/M-M vaccine-induced tumor growth inhibition and a Th1-prone cellular immune response, as well as reduce the individual differences of tumor growth and prolonged prophylactic and therapeutic mouse survival. Further research showed that MF59 promotes the maturation of DCs stimulated by CpG1826/M-M, resulting in Th1 polarization. The possible mechanism is speculated to be that MF59 could significantly prolong the retention time of CpG 1826, or the combination of CpG 1826 and M-M, as well as downregulate IL-6/STAT3 involved in MF59 combined CpG 1826-induced dendritic cell maturation. This study clarifies the utility of MF59/CpG 1826 as a vaccine compound adjuvant, laying the theoretical basis for the development of a novel M-M vaccine.

Breast Cancer Vaccine Containing a Novel Toll-like Receptor 7 Agonist and an Aluminum Adjuvant Exerts Antitumor Effects.

Mucin 1 (MUC1) has received increasing attention due to its high expression in breast cancer, in which MUC1 acts as a cancer antigen. Our group has been committed to the development of small-molecule TLR7 (Toll-like receptor 7) agonists, which have been widely investigated in the field of tumor immunotherapy. In the present study, we constructed a novel tumor vaccine (SZU251 + MUC1 + Al) containing MUC1 and two types of adjuvants: a TLR7 agonist (SZU251) and an aluminum adjuvant (Al). Immunostimulatory responses were first verified in vitro, where the vaccine promoted the release of cytokines and the expression of costimulatory molecules in mouse BMDCs (bone marrow dendritic cells) and spleen lymphocytes. Then, we demonstrated that SZU251 + MUC1 + Al was effective and safe against a tumor expressing the MUC1 antigen in both prophylactic and therapeutic schedules in vivo. The immune responses in vivo were attributed to the increase in specific humoral and cellular immunity, including antibody titers, CD4+, CD8+ and activated CD8+ T cells. Therefore, our vaccine candidate may have beneficial effects in the prevention and treatment of breast cancer patients.

Short-term cultured autologous peripheral blood mononuclear cells as a potential immunogen to activate Tax-specific CTL response in adult T-cell leukemia patients.

Activation of CD8+ Tax-specific CTL is a new therapeutic concept for adult T-cell leukemia (ATL) caused by HTLV-1. A recent clinical study of the dendritic cell vaccine pulsed with Tax peptides corresponding to CTL epitopes showed promising outcomes in ATL patients possessing limited human leukocyte antigen (HLA) alleles. In this study, we aimed to develop another immunotherapy to activate Tax-specific CTL without HLA limitation by using patients' own HTLV-1-infected cells as a vaccine. To examine the potential of HTLV-1-infected T-cells to activate CTL via antigen presenting cells, we established a unique co-culture system. We demonstrated that mitomycin C-treated HLA-A2-negative HTLV-1-infected T-cell lines or short-term cultured peripheral blood mononuclear cells (PBMC) derived from ATL patients induced cross-presentation of Tax antigen in co-cultured HLA-A2-positive antigen presenting cells, resulting in activation of HLA-A2-restricted CD8+ Tax-specific CTL. This effect was not inhibited by a reverse transcriptase inhibitor. IL-12 production and CD86 expression were also induced in antigen presenting cells co-cultured with HTLV-1-infected cells at various levels, which were improved by pre-treatment of the infected cells with histone deacetylase inhibitors. Furthermore, monocyte-derived dendritic cells induced from PBMC of a chronic ATL patient produced IL-12 and expressed enhanced levels of CD86 when co-cultured with autologous lymphocytes that had been isolated from the same PBMC and cultured for several days. These findings suggest that short-term cultured autologous PBMC from ATL patients could potentially serve as a vaccine to evoke Tax-specific CTL responses.

Co-immunization with L-Myc enhances CD8+ or CD103+ DCs mediated tumor-specific multi-functional CD8+ T cell responses.

Renal carcinoma shows a high risk of invasion and metastasis without effective treatment. Herein, we developed a chitosan (CS) nanoparticle-mediated DNA vaccine containing an activated factor L-Myc and a tumor-specific antigen CAIX for renal carcinoma treatment. The subcutaneous tumor models were intramuscularly immunized with CS-pL-Myc/pCAIX or control vaccine, respectively. Compared with single immunization group, the tumor growth was significantly suppressed in CS-pL-Myc/pCAIX co-immunization group. The increased proportion and mature of CD11c+ DCs, CD8+ CD11c+ DCs and CD103+ CD11c+ DCs were observed in the splenocytes from CS-pL-Myc/pCAIX co-immunized mice. Furthermore, the enhanced antigen-specific CD8+ T lymphocyte proliferation, cytotoxic T lymphocyte (CTL) responses, and multi-functional CD8+ T cell induction were detected in CS-pL-Myc/pCAIX co-immunization group compared with CS-pCAIX immunization group. Of note, the depletion of CD8 T cells resulted in the reduction of CD8+ T cells or CD8+ CD11c+ DCs and the loss of anti-tumor efficacy induced by CS-pL-Myc/pCAIX vaccine, suggesting the therapeutic efficacy of the vaccine was required for CD8+ DCs and CD103+ DCs mediated CD8+ T cells responses. Likewise, CS-pL-Myc/pCAIX co-immunization also significantly inhibited the lung metastasis of renal carcinoma models accompanied with the increased induction of multi-functional CD8+ T cell responses. Therefore, these results indicated that CS-pL-Myc/pCAIX vaccine could effectively induce CD8+ DCs and CD103+ DCs mediated tumor-specific multi-functional CD8+ T cell responses and exert the anti-tumor efficacy. This vaccine strategy offers a potential and promising approach for solid or metastatic tumor treatment.

Tumor-derived microparticles in tumor immunology and immunotherapy.

Microvesicles or microparticles, a type of cytoplasm membrane-derived extracellular vesicles, can be released by cancer cells or normal cell types. Alteration of F-actin cytoskeleton by various signals may lead to the cytoplasm membrane encapsulating cellular contents to form microparticles, which contain various messenger molecules, including enzymes, RNAs and even DNA fragments, and are released to extracellular space. The release of microparticles by tumor cells (T-MPs) is a very common event in tumor microenvironments. As a result, T-MPs not only influence tumor cell biology but also profoundly forge tumor immunology. Moreover, T-MPs can act as a natural vehicle that delivers therapeutic drugs to tumor cells and immune cells, thus, remodeling tumor microenvironments and resetting antitumor immune responses, thus, conferring T-MPs a potential role in tumor immunotherapies and tumor vaccines. In this review, we focus on the double-edged sword role of T-MPs in tumor immunology, specifically in TAMs and DCs, and emphasize the application of drug-packaging T-MPs in cancer patients. We aim to provide a new angle to understand immuno-oncology and new strategies for cancer immunotherapy.

Sustained IL-2R signaling of limited duration by high-dose mIL-2/mCD25 fusion protein amplifies tumor-reactive CD8+ T cells to enhance antitumor immunity.

High-dose IL-2 induces cancer regression but its therapeutic use is limited due to high toxicities resulting from its broad cell targeting. In one strategy to overcome this limitation, IL-2 has been modified to selectively target the intermediate affinity IL-2R that broadly activates memory-phenotypic CD8+ T and NK cells, while minimizing Treg-associated tolerance. In this study, we modeled an alternative strategy to amplify tumor antigen-specific TCR transgenic CD8+ T cells through limited application of a long-acting IL-2 fusion protein, mIL-2/mCD25, which selectively targets the high-affinity IL-2R. Here, mice were vaccinated with a tumor antigen and high-dose mIL-2/mCD25 was applied to coincide with the induction of the high affinity IL-2R on tumor-specific T cells. A single high dose of mIL-2/mCD25, but not an equivalent amount of IL-2, amplified the frequency and function of tumor-reactive CD8+ T effector (Teff) and memory cells. These mIL-2/mCD25-dependent effects relied on distinctive requirements for TLR signals during priming of CD8+ tumor-specific T cells. The mIL-2/mCD25-amplified tumor-reactive effector and memory T cells supported long-lasting antitumor responses to B16-F10 melanoma. This regimen only transiently increased Tregs, yielding a favorable Teff-Treg ratio within the tumor microenvironment. Notably, mIL-2/mCD25 did not increase non-tumor-specific Teff or NK cells within tumors, further substantiating the specificity of mIL-2/mCD25 for tumor antigen-activated T cells. Thus, the selectivity and persistence of mIL-2/mCD25 in conjunction with a tumor vaccine supports antitumor immunity through a mechanism that is distinct from recombinant IL-2 or IL-2-based biologics that target the intermediate affinity IL-2R.

The abscopal effect of radiation therapy.

Radiation therapy (RT) in some cases results in a systemic anticancer response known as the abscopal effect. Multiple hypotheses support the role of immune activation initiated by RT-induced DNA damage. Optimal radiation dose is necessary to promote the cGAS-STING pathway in response to radiation and initiate an IFN-1 signaling cascade that promotes the maturation and migration of dendritic cells to facilitate antigen presentation and stimulation of cytotoxic T cells. T cells then exert a targeted response throughout the body at areas not subjected to RT. These effects are further augmented through the use of immunotherapeutic drugs resulting in increased T-cell activity. Tumor-infiltrating lymphocyte presence and TREX1, KPNA2 and p53 signal expression are being explored as prognostic biomarkers.