bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional reprograming of chemokine microenvironment in colorectal cancer to promote intratumoral accumulation of immune effector cells
Authors: Kalinski Pawel , Zureikat Amer H. , Muthuswamy Ravikumar , Obermajer Natasa , Urban Julie , Butterfield Lisa H. , Gooding William , Zeh Herbert J. , Bartlett David L. 
Published: January 2023

Abstract
Infiltration of tumor lesions with effector CD8+ T cells (CTLs) has been shown to predict improved clinical outcomes in multiple cancer types and predict patients’ responsiveness to checkpoint blockers. In contrast, local prevalence of regulatory T(reg) cells has been shown to be a negative prognostic factor.
To correct the balance between intratumoral CTLs and Tregs in patients with advanced cancer, we developed a combinatorial approach to modify the balance between the CTL- and Treg-attracting chemokines in tumor tissues. Our preclinical studies in ex vivo tissue explant culture- and mouse tumor models, showed that TLR3 ligands combined with IFNα and PGE2 antagonists can reprogram tumor microenvironments to selectively promote the accumulation of CTLs and suppress Treg attraction.
Based on these preclinical data, we developed a phase I/II clinical trial (UPCI 10-131/NCT01545141), to determine the safety and local effectiveness of the intravenous infusion of Rintatolimod (selective TLR3 ligand) combined with Intron A and oral celecoxib, in patients with resectable recurrent colorectal cancer. In the completed phase I of this trial, we observed very good safety profile of this combination and, in accordance with our expectations, selective reduction in the markers of CTLs, TH1- and NK cells in circulation, lasting 24–48 hours after Rintatolimod and Intron A infusion. Comparison of the resected tumors demonstrated an enhanced ratio of CXCL10 (CTL-attractant) to CCL22 (Treg-attractant) and an increased ratio of CD8α (CTL marker) to FoxP3 (Treg marker), in the chemokine modulation cohort, compared to patients receiving standard care at our center (non-randomized control). The randomized phase II portion of the trial is ongoing.
The epigenetic cross-talk between tumor cells and immune microenvironment in colorectal cancer
Authors: Kryczek Ilona , Nagarsheth Nisha B , Peng Dongjun , Lin Yanwei , Wei Shuang , Zhao Ende , Huang Emina , Zhao Lili , Vatan Linda , Szeliga Wojciech , Zou Weiping 
Published: January 2023

Abstract
Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation and influence the local anti-tumor immune response. In this study, we examined the relationship between the H3K27me3 and effector T-cell trafficking. We showed that H3K27me3 repress the tumor production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumor microenvironment. On the other hand, local trafficking in response to CCR6/CCL20 ligation is associated with increased Th22 phenotype. Th22 derived IL-22 activates DOT1L complex which turned on stem cell gene expression, increased cancer stemness, and promoted tumorigenic potential. The knowledge about the alterations in the epigenetic landscape of colorectal cancer may lead to understand colon cancer immunology and design effective treatments.
Immunosuppression limits CD8+ T cell entry into subcutaneous B16 melanoma
Authors: Wilson Ashley Lauren , Woods Amber N. , Engelhard Victor H. 
Published: January 2023

Abstract
Interactions between homing receptors (HR) and ligands on the vasculature facilitate effector CD8 T cell entry into tissues. HR ligand expression on normal inflamed tissue vasculature is induced by the local release of pro-inflammatory cytokines. In tumors, however, it is likely that expression of HR ligands on tumor vasculature is suboptimal due to immunosuppression. We hypothesized that disruption of immunosuppression would increase HR ligand expression on tumor vasculature, and consequently, enhance CD8 T cell entry. B16-F1 melanoma tumor-bearing mice were treated with blocking antibodies against CTLA-4 or PD-1. HR ligand expression on tumor vasculature and CD8 T cell representation were assessed. We found that CTLA-4 or PD-1 blockade significantly increased intravascular CXCL9 expression in subcutaneous B16-F1 tumors. Unlike PD-1 blockade, CTLA-4 blockade was associated with increased E-selectin expression on tumor vasculature, which we have shown to be important for CD8 T cell entry into subcutaneous tumors. CTLA-4 blockade also enhanced CD8 T cell representation and reduced tumor size. We observed a very low percentage of PD-1+ CD8 T cells in B16-F1 tumors, which may account for the limited efficacy of PD-1 blockade. Interestingly, the percentage of intratumoral PD-1+ CD8 T cells increased post-treatment with anti-CTLA-4. Our data suggest that CTLA-4 blockade may act to enhance T cell priming in the lymph node to increase the number of CD8 T cell effectors available to infiltrate tumors. It is also possible that CTLA-4 blockade may act on CTLA-4+ intratumoral Tregs, thereby promoting reactivation of tumor-resident CD8 T cell effectors that secrete pro-inflammatory cytokines that upregulate HR ligands on tumor vasculature.
Immunomodulation mediated by anti-angiogenic therapy improves viral vaccination against GL261 glioma tumors.
Authors: Malo Courtney Sarah , Renner Danielle N , Jin Fang , Hansen Michael J , Pavelko Kevin D , Johnson Aaron J 
Published: January 2023

Abstract
Glioblastoma multiforme (GBM) is a lethal cancer of the central nervous system with a median survival rate of 15 months with treatment. Thus, there is a critical need to develop novel therapies for GBM. Immunotherapy is emerging as a promising therapeutic strategy. However, current standard-of-care therapies for GBM, in particular anti-angiogenic therapies that block vascular endothelial growth factor (VEGF), may have undefined consequences on the efficacy of immunotherapy. While this treatment is primarily prescribed to reduce tumor vascularization, multiple immune cell types also express VEGF receptors, including the most potent antigen‑presenting cell, the dendritic cell (DC). Therefore, we assessed the role of anti-VEGF therapy in combination with a novel tumor antigen-specific picornaviral vaccination in the GL261 syngeneic murine model of glioma. We hypothesized that treatment of GL261 glioma-bearing mice with anti‑VEGF therapy will act synergistically with anti-tumor picornaviral vaccination by enhancing DC maturation. We found that VEGF blockade results in a more mature DC phenotype in the brain and tumor-draining lymph node, as demonstrated by an increase in the expression of the co‑stimulatory molecules B7-1 and B7-2. Furthermore, we observed an increase in brain infiltrating, tumor antigen-specific CD8 T cells. This change in immune response directly correlates with a significant reduction in tumor burden, as measured by bioluminescence imaging, and a significantly improved survival rate of mice receiving both anti-VEGF therapy and viral vaccination compared to either treatment alone. Thus, anti-angiogenic therapy can be used in conjunction with and enhance immunotherapy for GBM.
Chemotherapy-derived inflammatory responses promote the differentiation and immunosuppressive activity of monocytic-MDSC
Authors: Ding Chuanlin , Yan Jun 
Published: January 2023

Abstract
Emerging evidence has unveiled the contribution of tumor microenvironment to the regulation of chemotherapeutic outcomes. However, the impact of chemotherapy on anti-tumor immunity and immunosuppression still remains elusive. In this study, we investigated the role of chemotherapy-derived inflammatory responses in the differentiation of myeloid-derived suppressive cells (MDSC). The anti-cancer agents Gemcitabine and Carboplatin induced the activation of MAPK pathway in mouse mammary cancer cell line EO771 and also stimulated cytokine and chemokine production including GM-CSF and IL-6. The supernatants of Gemcitabine-treated tumor cells promoted more bone marrow-derived monocytic MDSC differentiation, and enhanced their immunosuppressive activity on effector T cells. The expression of MDSC associated molecules such as Arginase and iNOS significantly increased in M-MDSC induced by the supernatant of Gemcitabine-treated tumor cells. In vivo treatment of EO771 tumors with Gemcitabine increased the suppressive function of MDSC. Our findings also suggest that Dectin-1 activation by β-glucan could significantly reduce MDSC suppressive function. Together, these results describe a role of chemotherapy-derived inflammation in the modification of chemotherapy-treated tumor microenvironment and suggest the targeting of Dectin-1 signaling may benefit cancer patients by reprogramming MDSC in chemotherapy setting.
Peripheral Reprogrammed CD4+ CTL Efficiently Control Tumor Growth.
Authors: Thiault Nicolas , Husain Mushtaq , Iwaya Hitoshi , Cheroutre Hilde 
Published: January 2023

Abstract
The initial commitment to either the CTL- or Th-lineage is made during thymic development, where thymocytes expressing an MHC class II–reactive TCR commit to the CD4 helper T cell lineage, whereas thymocytes with specificity for MHC class I differentiate into the CD8 CTL lineage. The molecular regulation is controlled by the action and counteraction of transcription factors, such as t ThPOK, which promotes the Th fate and Runx3 which drives the differentiation of MHC class I restricted thymocytes into the CD8 CTL-lineage. This dichotomy persists in the periphery, where ThPOK continues to suppress the cytotoxic fate of MHC class II–restricted CD4+ Th cells. Recently, our team made a major breakthrough and showed that the thymic lineage commitment of CD4 Th cells is not fixed and that mature peripheral CD4+ T cells have the plasticity to lose ThPOK expression.
We demonstrated that the loss of Thpok expression and the Th fate coincides with the re-expression of CD8α and the induction of a typical CTL phenotype, including 2B4 and Granzyme B expression and IFN-γ and TNF-α cytokine production. Using an in vitro cytotoxic assay, our lab found that these reprogrammed ThPOK− CD4+ T cells display killer capacities.
In a new study we now investigate the role of CD4 CTL in anti-tumor immune surveillance. Using the well-described B16-melanoma tumor model, we demonstrated that in vitro differentiated OVA-specific CD4 CTL display anti-tumor capacity and efficiently killed OVA-expressing B16 tumor cells.
This studies on CD4 CTL in the cancer field will not only greatly expand our basic understanding of anti-tumor immunity but it will undoubtedly have major implications for translational research to design new cell therapies to treat devastating cancers.
Dissecting the use of recipient alloreactive responses to achieve anti-leukemic effect
Authors: Fast Loren D , Nevola Martha , Reagan John 
Published: January 2023

Abstract
Harnessing alloreactive responses to incur anti-leukemic effects has focused on the donor lymphocyte response directed toward recipient antigens. Limited studies have examined the anti-leukemic potential of recipient alloreactive responses to donor cell antigens. An example is the infusion of large numbers of haploidentical, G-CSF mobilized, donor T cells (1 – 2 × 108 CD3+ cells/kg) into patients with refractory hematological malignancies who had received100 cGy total body irradiation prior to infusion. Strong recipient immune responses were generated capable of eliminating the donor cells within two weeks (thereby preventing GVHD) with side effects of high fever (104°F), malaise, rash, and diarrhea. More than half of these patients also generated responses to the hematological malignancies(14/26, 9 major), including some complete remissions. The protocol was modified in the reopened clinical trial by elimination of both the G-CSF mobilization of donor cells and the recipient 100 cGy total body irradiation. These patients exhibited milder, self-resolving fevers and limited anti-leukemic responses (1/5 with transient response). Analysis of blood samples obtained at several different timepoints after infusion revealed diminished IL-6 levels. Increased levels of plasma IL-2 and granzyme B and increased expression of granzyme B and PD-1 by activated recipient T cells correlated with elimination of donor cells. Increased expression of PD-1 ligands on leukemic cells provides one explanation for the lack of anti-leukemic response. These results indicate that appropriate manipulation of both donor cells and patients in this protocol should improve the anti-leukemic responses of recipient lymphocytes.
Age and sex affect αCTLA-4 efficacy alone and combined with αB7-H1 or regulatory T cell depletion in a melanoma model.
Authors: Figueiredo Alvaro Souto Padron , Hurez Vincent , Liu Aijie , Curiel Tyler J 
Published: January 2023

Abstract

Background
Most cancer patients are aged but most preclinical studies are in young hosts. We tested age effects on immunotherapy to further our understanding and identify strategies.

Methods
Young (3 mos) and aged (~26 mos) BL6 mice were injected subcutaneously with syngeneic B16 melanoma cells. 7 days later, mice got 2 μg denileukin diftitox (DD), an FDA-approved IL-2/diphtheria toxin or 200 μg αCD25 (both to deplete Tregs) ± 50 μg αCTLA-4 or 100 μg αB7-H1. 5 days later mice got a 2nd treatment.

Results
αCTLA-4 depleted intra-tumor Tregs in young but not aged males, a major age effect. In young BL6 males or females αCTLA-4 + αB7-H1 rejected B16 tumors better than either single agent. In aged males, αCTLA4 + αB7-H1 treated B16, but surprisingly accelerated tumors in aged females. Individual agents were effective in young hosts but had negligible effects in the aged. αCTLA-4 + either DD or αCD25 to deplete Tregs significantly reduced tumor growth in young mice but DD was better than αCD25. Neither combo treated B16 in aged mice. This DD dose did not deplete Tregs in aged mice as well as young, but higher DD doses were equally effective. In support, in Foxp3DTR mice, in which we deplete ~100% Treg (versus 20–50% with DD or αCD25), aged mice potently rejected B16.

Conclusions
Cancer immunotherapy studies in young give an incomplete understanding of clinical effects and mechanisms in the aged most at risk for cancer. We identify major Treg effects and differential Treg depletion efficacy of αCTLA4 and DD contributing to treatment failures in the aged and means to mitigate effects. With appropriate treatments, even very old mice can mount effective anti-tumor immunity. Novel sex differences in aged are unlikely estrogen-related and require further study.
A topical chemo-immunotherapy for squamous cell carcinoma.
Authors: Friedman Blake , Donahue Cara , Erdos Geza , Falo Louis D 
Published: January 2023

Abstract
We have previously demonstrated that dissolvable microneedle arrays can co-deliver cargos directly to the skin while avoiding systemic distribution. As squamous cell carcinoma (SCC) has a lifetime incidence of 7–11% in the United States and is the second most common non-melanoma skin cancer in persons of white European descent, we sought to determine if MNA delivery of anti-tumor agents induce cell death and improve survival in a mouse model of SCC and in freshly excised human SCCs. To accomplish this, we evaluated the effectiveness of doxorubicin, a chemotherapeutic demonstrated to induce immunogenic cell death, as an MNA delivered therapeutic. Effectiveness was evaluated in mice inoculated with SCC cells and later treated with Blank MNAs (MNA-Blank) or MNAs integrating doxorubicin (MNA-Dox), and in human SCCs treated with MNA-Dox. In mice, MNA-Dox treatment resulted in increased levels of pro-inflammatory cytokine gene expression, increased levels of cell death as determined by TUNEL assays, attenuated tumor growth, and substantially improved survival over MNA-Blank treatment at 20 days post-inoculation (100% survival in MNA-Dox group versus 0% survival in MNA-Blank group). Survival advantage persisted with 40% of MNA-Dox-treated mice alive at 40 days post-inoculation. Similarly, freshly excised human SCCs treated with MNA-Dox demonstrated increased levels of cell death as determined by TUNEL assays. Taken together, these results demonstrate the potential of MNA administration of doxorubicin to effectively induce tumor cell death in a murine model of squamous cell carcinoma and in human SCCs supporting further clinical development.
CD26 expression on T helper cells correlates with cell persistence and antitumor activity in vivo
Authors: Bailey Stefanie R , Nelson Michelle , Butcher Aubrey , Bowers Jacob , Meek Megan , Neal Lillian , Paulos Chrystal 
Published: January 2023

Abstract
Adoptive T cell transfer has been an impressive therapy for treating cancer patients, but can be inconsequential if the transferred cells are unable to engraft and persist. Our lab has found that human CD4+ T cells that express intermediate or high levels of CD26—termed CD26intermediate and CD26high T cells, respectively—display striking antitumor activity in NSG mice bearing large, established mesothelioma. Importantly, these cells also exhibit increased engraftment and persistence compared to mice treated with bulk CD4+ or CD26negative T cells. While the multi-functional nature (IL-17, IFN-γ, IL-2, TNF-α, IL-22) and heightened cytotoxicity (CD107A, Granzyme B) of CD26high T cells can help explain their antitumor activity in vivo, their ability to persist despite their effector memory phenotype is intriguing. After further evaluation, we found that both CD26intermediate and CD26highT cells express elevated β-catenin and BCL-2, as well as decreased Caspase 3 cleavage, compared to CD4+ and CD26negative T cells. Excitingly, both CD26intermediate and CD26high T cells continued to display enhanced T cell persistence and significantly delayed tumor growth when transferred into mice bearing aggressive PANC1 pancreatic tumors. Furthermore, mice treated with bulk CD26+ T cells also displayed a better antitumor response than those treated with bulk CD4+ or CD26negative T cells. Strikingly, these effects were all seen in the absence of cytotoxic CD8+ T cells, which have often been thought to be crucial for effective antitumor responses. Overall, this data suggests that the presence of CD26 on transferred CD4+ T cells could be crucial for an effective antitumor response and can be utilized to enhance future immunotherapy strategies.
Hepatitis C virus-cross-reactive TCR gene-modified T cells: A model for immunotherapy against diseases with genomic instability
Authors: Spear Timothy T , Riley Timothy , Foley Kendra C , Murray David C , Simms Patricia E , Scurti Gina M , Wang Yuan , Hellman Lance M , McMahan Rachel H , Rosen Hugo R , Baker Brian M , Nishimura Michael I 
Published: January 2023

Abstract
A major obstacle hindering the development of effective immunity against viral infections, their associated disease, and certain cancers is their genomic instability. Accumulation of mutations can alter processing/presentation of antigens recognized by antibodies and T cells leading to immune escape variants. A therapeutic agent that can combat rapidly mutating viral or cancer-associated antigens would be advantageous in providing effective immunity. We propose T cells harboring cross-reactive TCRs may offer a solution in these instances. Using hepatitis C virus (HCV), known for its genomic instability, as a model for mutant antigen recognition, we demonstrate cross-reactivity of TCRs against immunogenic and mutagenic NS3:1406-1415 and NS3:1073-1081 epitopes in TCR-gene-modified T cells. Our approach includes (1) functional studies demonstrating crossreactive profiles; (2) epidemiological data supporting the relevance of mutant epitope prevalence in infected individuals; (3) TCR-pMHC structural modeling to rationalize how TCR structural properties accommodate recognition of certain mutated epitopes and how they impact the requirement of CD8; lastly, we (4) provide preliminary clinical evidence of cross-reactive TCR benefit in that T cell clones isolated from HCV-infected patients who spontaneously resolved infection exhibited broader cross-reactivity compared to those of individuals with chronic infection. Together this approach serves as a model to address diseases with genomic instability and highlights potential benefit of cross-reactive TCRs. A better understanding of such TCRs’ promiscuous behavior may allow for exploitation of these properties to develop novel adoptive T cell-based therapies.
Th17 cells retain antitumor efficacy after long-term ex vivo expansion
Authors: Bowers Jacob S , Nelson Michelle , Majchrzak Kinga , Bailey Stefanie R , Diven Marshall , Schwartz Kristina , Rohrer Baerbel , Gattinoni Luca , Paulos Chrystal 
Published: January 2023

Abstract
Immunotherapies have produced impressive responses in melanoma patients by re-training their immune system to fight their cancer. One of the most successful of these methods is adoptive T cell therapy (ACT), which enriches, expands, and educates a patient’s tumor-reactive T cells before returning them to the patient. This therapy depends on infusing large numbers of cells (upwards of 1010 cells/patient) to mediate tumor regression, while also requiring cells of durable quality capable of sustaining long-term remission. Unfortunately, CD8+ T cells which are most often used, lose their antitumor efficacy as they are expanded ex vivo to large numbers. To circumvent this dilemma, we propose the use of IL-17 producing CD4+ T cells (Th17 cells), for ACT. We found that similar to CD8+ T cells, treatment with Th17 cells was more effective with higher numbers. These numbers can be achieved as Th17 cells expanded up to 10,000 fold after three weeks of ex vivo culture. At the end of culture, Th17 cells were as effective at eradicating melanomas as Th17 cells cultured for shorter duration. Between early and late culture time points, Th17 cells retained an effector memory phenotype (CD44+CD62L−) without acquiring markers of full effector and exhausted status, converted to a Th1-like functional profile (from mainly secreting IL17 to co-secreting IFNγ and IL17), and maintained the ability to engraft and persist in the host. We also demonstrate the power of combining the high yield and durable potency of Th17 cells by using their total yield at late culture to control clinically significant end-stage disease. These results support the advancement of Th17 cells to clinical trials to increase the number, quality, and duration of patient responses to treatment.
CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells
Authors: Rupp Levi , Schumann Kathrin , Roybal Kole T , Marson Alexander , Lim Wendell A 
Published: January 2023

Abstract
Immunotherapies with chimeric antigen receptor (CAR) T cells and checkpoint inhibitors (including antibodies that antagonize the programmed cell death protein 1 [PD-1] pathway) have both opened new avenues for cancer treatment, but the clinical potential of combination checkpoint blockade and CAR T cell therapy remains incompletely explored. Here we show that programmed death ligand 1 (PD-L1) expression on tumor cells can render human CAR T cells (anti-CD19 4-1BBζ) hypo-functional, resulting in impaired tumor clearance in a sub-cutaneous mouse xenograft model. To overcome this suppressed anti-tumor response, we developed a protocol for combined Cas9 ribonucleoprotein (Cas9 RNP)-mediated gene editing and lentiviral transduction to generate PD-1 deficient, anti-CD19 CAR T cells. PD-1 disruption augmented CAR T cell mediated killing of tumor cells in vitro and enhanced clearance of PD-L1+ tumor xenografts in vivo. This study demonstrates improved therapeutic efficacy of Cas9-edited human CAR T cells and highlights the potential of precision genome engineering to enhance next-generation cell therapies and uncover mechanisms regulating human immune cell function.