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Betul Gok Yavuz,1 Elshad Hasanov,2 Sunyoung S Lee,1 Yehia I Mohamed,1 Michael A Curran,3 Eugene J Koay,4 Vittorio Cristini,5,6 Ahmed O Kaseb1 1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 5Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX, USA; 6Department of Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX, USACorrespondence: Ahmed O Kaseb Email akaseb@mdanderson.orgAbstract: Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Multiple immunotherapeutic approaches have been investigated to date, and immunotherapy has become the new standard of care therapy in HCC. However, the current role of immunotherapy in HCC remains non-curative. Given this context, a high priority for oncology is understanding the biomarkers that predict clinical response to immunotherapy, have the potential to improve patient selection to maximize the clinical benefit, and spare unnecessary toxicity. In this review, we summarize the key predictive and prognostic biomarkers investigated in immunotherapy clinical trials in HCC and the emerging biomarkers to serve as a roadmap for future clinical trials. Biomarkers from tumoral tissues including PDL-1 expression, tissue infiltrating lymphocytes, tumor mutational burden (TMB) and specific immune signatures, and from peripheral blood including neutrophil-to-lymphocytes ratio, platelet-to-lymphocytes ratio, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and specific cytokines, along with gut microbiota are among the studied biomarkers to date in the HCC era. More integrative approaches, including mathematical biomarkers to predict immunotherapy outcomes, are yet to be studied in HCC.Keywords: hepatocellular carcinoma, immunotherapy, biomarker

Immune-mediated gene therapy using adenovirus expressing Flt3 ligand and thymidine kinase followed by ganciclovir administration (Flt3/TK) effectively elicits tumor regression in preclinical glioma models. Herein, we assessed new strategies to optimize Flt3L/TK therapeutic efficacy in a refractory RG2 orthotopic glioblastoma model. Specifically, we aimed to optimize the therapeutic efficacy of Flt3L/TK treatment in the RG2 model by overexpressing the following genes within the brain tumor microenvironment: 1) a TK mutant with enhanced cytotoxicity (SR39 mutant TK), 2) Flt3L-IgG fusion protein that has a longer half-life, 3) CD40L to stimulate DC maturation, 4) T helper cell type 1 polarizing dendritic cell cytokines interleukin-12 or C-X-C motif ligand 10 chemokine (CXCL)-10, 5) C-C motif ligand 2 chemokine (CCL2) or C-C motif ligand 3 chemokine (CCL3) to enhance dendritic cell recruitment into the tumor microenvironment, 6) T helper cell type 1 cytokines interferon-γ or interleukin-2 to enhance effector T-cell functions, and 7) IκBα or p65RHD (nuclear factor kappa-B [NF-κB] inhibitors) to suppress the function of Foxp3+ Tregs and enhanced effector T-cell functions. Anti-tumor immunity and tumor specific effector T-cell functions were assessed by cytotoxic T lymphocyte assay and intracellular IFN-γ staining. Our data showed that overexpression of interferon-γ or interleukin-2, or inhibition of the nuclear factor kappa-B within the tumor microenvironment, enhanced cytotoxic T lymphocyte-mediated immune responses and successfully extended the median survival of rats bearing intracranial RG2 when combined with Flt3L/TK. These findings indicate that enhancement of T-cell functions constitutes a critical therapeutic target to overcome immune evasion and enhance therapeutic efficacy for brain cancer. In addition, our study provides novel targets to be used in combination with immune-therapeutic strategies for glioblastoma, which are currently being tested in the clinic. [ABSTRACT FROM AUTHOR]

An electronic reserve room is ideal for attaining currency of readings and simplified distribution. This article explores issues of copyright and the best ways to transfer materials to a digital format. [ABSTRACT FROM AUTHOR]

Blockade of the immune checkpoints programmed death-1 (PD-1) and cytotoxic lymphocyte antigen 4 has improved outcomes for patients with hepatocellular carcinoma (HCC), yet most still fail to achieve objective clinical benefit. MET plays key roles in both HCC tumorigenesis and immunosuppressive conditioning; however, inhibition of MET causes upregulation of PD-ligand 1 (PD-L1) suggesting the use of these inhibitors in the context of PD-1 blockade. We sought to investigate across the Hepa1-6, HCA-1 and diethylnitrosamine (DEN) models of HCC whether the combination of more specific type I versus more pleiotropic type II MET inhibitors would confer superior outcomes in combination with PD-1 blockade. While MET inhibition demonstrated cooperativity with αPD-1 across all three models, the type I MET inhibitor capmatinib showed optimal activity in combination and statistically significantly outperformed the combination with the type II inhibitor cabozantinib in the αPD-1 refractory DEN model. In both HCA-1 and DEN HCC, the capmatinib and αPD-1 combination enhanced CD8 T cell frequency and activation state while limiting intratumoral myeloid immune suppression. In vitro studies of antigen-specific T cell activation reveal significantly less inhibition of effector cytokine production and proliferation by capmatinib versus by type II or type III MET inhibitors. These findings suggest significant potential for clinical HCC combination studies of type I MET inhibitors and PD-1 blockade where prior trials using type II inhibitors have yielded limited benefit., Competing Interests: Competing interests: MAC reports grants and personal fees from ImmunoGenesis, personal fees from Alligator Bioscience, ImmunOs, OncoResponse, Kineta, Xencor, Agenus, AstraZeneca outside the submitted work; In addition, MAC has a patent “Dual specificity antibodies which bind both PD-L1 and PD-L2 and prevent their binding to PD-1” with royalties paid by ImmunoGenesis., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The field of immunology has traditionally focused on immune checkpoint modulation of adaptive immune cells. However, many malignancies such as glioblastoma are mostly devoid of T cells and rather are enriched with immunosuppressive myeloid cells of the innate immune system. While some immune checkpoint targets are shared between adaptive and innate immunity, myeloid-specific checkpoints could also serve as potential therapeutics. To better understand the impact of immune checkpoint blockade on myeloid cells, we systematically summarize the current literature focusing on the direct immunological effects of PD-L1/PD-1, CD24/Siglec-10, collagen/LAIR-1, CX3CL1/CX3CR1, and CXCL10/CXCR3. By synthesizing the molecular mechanisms and the translational implications, we aim to prioritize agents in this category of therapeutics for glioblastoma., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Perioperative immunotherapy has shown promise in some patients with early-stage hepatocellular carcinoma (HCC). This study examined tissue and imaging biomarkers associated with pathologic response in a phase II clinical trial in patients with resectable HCC., Methods: Analysis included 18 patients with biopsy-proven resectable HCC treated with neoadjuvant nivolumab plus ipilimumab or nivolumab alone in a phase II clinical trial at MD Anderson Cancer Center (NCT03222076). Liver MRE (to measure tissue fibrosis) and biopsies (to evaluate immune activation markers) were obtained serially pretreatment and after completing neoadjuvant immunotherapy. A major pathologic response (MPR) was defined as tumor necrosis of more than 70%. Data comparing patients with MPR versus those without were summarized using descriptive statistics and compared using the Wilcoxon rank-sum test., Results: Patients with MPR after neoadjuvant immunotherapy tended to have larger tumors (mean 9.52 vs. 4.99 centimeters; p = 0.050). They had a significant reduction in tumor size posttreatment (14.67% reduction vs. 9.15% increase in size; p = 0.042) and a nonsignificant decrease in serum AFP (-24.20% vs. -14.00%; p = 0.085). Further, patients with MPR had a greater increase in intratumoral expression levels of CD8 (26.92% vs. -0.04%; p = 0.026), granzyme B (15.56% vs. -2.24%; p = 0.011), and PD-1 (20.17% vs. 0.40%; p = 0.048) but not PD-L1 (7.69% vs. 0.57%; p = 0.26). For imaging biomarkers, tumor and liver fibrosis were comparable before and after neoadjuvant therapy in patients with MPR versus nonresponders., Conclusion: Changes in tumor size, immune cell infiltration, and immune cell activation are candidate predictive markers of pathologic response to neoadjuvant immunotherapy in patients with resectable HCC., (© 2024 S. Karger AG, Basel.)

Background/aims: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge., Methods: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab., Results: The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of antitumor macrophages and activated T-cells, potentially explaining its better response., Conclusion: Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.

Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 in a STAT3-dependent manner, leading to the efflux of bone marrow neutrophils to the circulation and damaged liver. Cholesterol, via its receptor ERRα, stimulates neutrophils to secrete hepatocyte growth factor to accelerate hepatocyte proliferation. Altogether, our findings reveal a LIFR-STAT3-CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-ERRα-hepatocyte growth factor axis that form bidirectional hepatocyte-neutrophil cross-talk to repair and regenerate the liver., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation.

Lack of robust activation of Stimulator of Interferon Genes (STING) pathway and subsequent induction of type I IFN responses is considered a barrier to antitumor immunity in acute myeloid leukemia (AML). Using common human AML cell lines as in vitro tools to evaluate the efficacy of novel STING agonists, we found most AML lines to be poor producers of IFNs upon exposure to extremely potent agonists, suggesting cell-intrinsic suppression of STING signaling may occur. We observed unexpected patterns of response that did not correlate with levels of STING pathway components or of known enzymes associated with resistance. To identify a genetic basis for these observations, we cloned and sequenced STING from the cDNA of human AML cell lines and found both frequent mutations and deviations from normal RNA splicing. We identified two novel spliced isoforms of STING in these lines and validated their expression in primary human AML samples. When transduced into reporter cells, these novel STING isoforms exhibited complete insensitivity to agonist stimulation. These observations identify alternative splicing as a mechanism of STING pathway suppression and suggest that most AML silences the STING pathway through direct modification rather than through engagement of external inhibitory factors., Significance: We find that AML acquires resistance to innate immune activation via the STING pathway through aberrant splicing of the STING transcript including two novel forms described herein that act as dominant negatives. These data broaden understanding of how cancers evolve STING resistance, and suggest that the AML tumor microenvironment, not the cancer cell, should be the target of therapeutic interventions to activate STING., (© 2024 The Authors; Published by the American Association for Cancer Research.)

We previously showed that ablation of tumor hypoxia can sensitize tumors to immune checkpoint blockade (ICB). Here, we used a Kras+/G12D TP53+/R172H Pdx1-Cre-derived (KPC-derived) model of pancreatic adenocarcinoma to examine the tumor response and adaptive resistance mechanisms involved in response to 2 established methods of hypoxia-reducing therapy: the hypoxia-activated prodrug TH-302 and vascular endothelial growth factor receptor 2 (VEGFR-2) blockade. The combination of both modalities normalized tumor vasculature, increased DNA damage and cell death, and delayed tumor growth. In contrast with prior cancer models, the combination did not alleviate overall tissue hypoxia or sensitize these KPC tumors to ICB therapy despite qualitative improvements to the CD8+ T cell response. Bulk tumor RNA sequencing, flow cytometry, and adoptive myeloid cell transfer suggested that treated tumor cells increased their capacity to recruit granulocytic myeloid-derived suppressor cells (G-MDSCs) through CCL9 secretion. Blockade of the CCL9/CCR1 axis could limit G-MDSC migration, and depletion of Ly6G-positive cells could sensitize tumors to the combination of TH-302, anti-VEGFR-2, and ICB. Together, these data suggest that pancreatic tumors modulate G-MDSC migration as an adaptive response to vascular normalization and that these immunosuppressive myeloid cells act in a setting of persistent hypoxia to maintain adaptive immune resistance.

Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years. Trials evaluating novel immunotherapeutic approaches, such as targeting the programmed death-1 (PD-1) pathway, have unfortunately not yielded comparable results to those seen in solid tumors. Major histocompatibility complex (MHC) proteins are cell surface proteins essential for the adaptive immune system to recognize self versus non-self. MHC typing is used to determine donor compatibility when evaluating patients for HSCT. Recently, loss of MHC class II (MHC II) was shown to be a mechanism of immune escape in patients with acute myeloid leukemia after HSCT. Here we report that treatment with the tyrosine kinase inhibitor, dasatinib, and an anti-PD-1 antibody in preclinical models of Philadelphia chromosome positive B-cell acute lymphoblastic leukemia is highly active. The dasatinib and anti-PD-1 combination reduces tumor burden, is efficacious, and extends survival. Mechanistically, we found that treatment with dasatinib significantly increased MHC II expression on the surface of antigen-presenting cells (APC) in a tumor microenvironment-independent fashion and caused influx of APC cells into the leukemic bone marrow. Finally, the induction of MHC II may potentiate immune memory by impairing leukemic engraftment in mice previously cured with dasatinib, after re-inoculation of leukemia cells. In summary, our data suggests that anti-PD-1 therapy may enhance the killing ability of dasatinib via dasatinib driven APC growth and expansion and upregulation of MHC II expression, leading to antileukemic immune rewiring., Competing Interests: Competing interests: PK reports advisory board fees from Novartis, Daiichi Sankyo, BMS, and Ascentage, the speaker’s bureau of Takeda and Novartis, reports participating in the data safety monitoring board with Treadwell Therapeutics, and honoraria with Clinical Care Targeted Communications. PW reports employment from Genentech. MAC reports grants and personal fees from ImmunoGenesis, Inc., personal fees from Alligator Bioscience, Inc., personal fees from ImmunOS, Inc., grants and personal fees from ImmunoMet, Inc., personal fees from Oncoresponse, Inc., personal fees from Pieris, Inc., personal fees from Nurix, Inc., personal fees from Aptevo, Inc., personal fees from Servier, Inc., personal fees from Kineta, Inc., personal fees from Salarius, Inc., personal fees from Xencor, Inc., personal fees from Agenus, Inc., personal fees from Mereo, Inc., personal fees from Amunix, Inc., personal fees from Adagene, Inc., outside the submitted work. In addition, MAC has a patent Methods and Composition for Localized Secretion of Anti-CTLA-4 Antibodies with royalties paid to multiple licensees, a patent Dual specificity antibodies which bind both PD-L1 and PD-L2 and prevent their binding to PD-1 with royalties paid to ImmunoGenesis, Inc., and a patent Cyclic Dinucleotides as Agonists of Stimulator of Interferon Gene Dependent Signaling licensed to ImmunoGenesis, Inc. MK reports grants from Ablynx, Agios, Ascentage, AstraZeneca, Calithera, Cellectis, Eli Lilly, Rafael Pharmaceutical, and Sanofi; grants and other support from AbbVie, F. Hoffman La-Roche, Forty-Seven, Genentech, and Stemline Therapeutics; and other support from Amgen, Kisoji, Reata Pharmaceutical outside the submitted work; and has a patent (US 7,795,305 B2: “CDDO-Compounds and Combination Therapie”) with royalties paid to Reata Pharm, a patent (“Combination Therapy With a Mutant IDH1 Inhibitor and a BCL-2”) licensed to Eli Lilly, and a patent (62/993,166: Combination of a MCL-1 Inhibitor and Midostaurin, Uses and Pharmaceutical Compositions Thereof”) pending to Novartis. Funding for this work was provided by the Advanced Scholar Program at MD Anderson (2018-2019, Koller), the University of Texas MD Anderson Cancer Center support Grant (CA016672), and the University of Texas MD Anderson–China Medical University and Hospital Sister Institution Network Fund., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlate with body mass index (BMI), and serum SNORD46 antagonizes interleukin-15 (IL-15) signaling. Mechanically, SNORD46 binds IL-15 via G11, and G11A (a mutation that significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL-15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In natural killer (NK) cells, SNORD46 suppresses the IL-15-dependent autophagy, leading to reduced viability of obese NK. SNORD46 power inhibitors exhibit anti-obesity effects, concurring with improved viability of obese NK and anti-tumor immunity of CAR-NK cell therapy. Hence, our findings demonstrate the functional importance of snoRNAs in obesity and the utility of snoRNA power inhibitors for antagonizing obesity-associated immune resistance., Competing Interests: Declaration of interests M.A.C. reports grants and personal fees from ImmunoGenesis, Inc. and personal fees from Alligator Bioscience, Inc.; ImmunOS, Inc.; Oncoresponse, Inc.; Nurix, Inc.; Aptevo, Inc.; Kineta, Inc.; Xencor, Inc.; Agenus, Inc.; Adagene, Inc.; and Astrazeneca, Inc. outside the submitted work. K.R. and the University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Takeda Pharmaceutical and Affimed GmbH. K.R. participates on the Scientific Advisory Board for GemoAb, AvengeBio, Virogin Biotech, GSK, Caribou Biosciences, Navan Technologies, and Bayer. B.G. is an inventor on patent applications involving targeting ferroptosis in cancer therapy and reports personal fees from Guidepoint Global, Cambridge Solutions, and NGM Bio., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We, therefore, developed murine glioblastoma stem cell lines derived from Nestin-CreERT2QkL/L; Trp53L/L; PtenL/L (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and their underlying mechanisms., Methods: The differential responsiveness of QPP lines was assessed in the brain and flank in untreated, anti-PD-1, or anti-CTLA-4 treated mice. The impact of genomic landscape on the responsiveness of each tumor was measured through whole exome sequencing. The immune microenvironments of sensitive (QPP7) versus resistant (QPP8) lines were compared in the brain using flow cytometry. Drivers of flank sensitivity versus brain resistance were also measured for QPP8., Results: QPP lines are syngeneic to C57BL/6J mice and demonstrate varied sensitivities to T cell immune checkpoint blockade ranging from curative responses to complete resistance. Infiltrating tumor immune analysis of QPP8 reveals improved T cell fitness and augmented effector-to-suppressor ratios when implanted subcutaneously (sensitive), which are absent on implantation in the brain (resistant). Upregulation of PD-L1 across the myeloid stroma acts to establish this state of immune privilege in the brain. In contrast, QPP7 responds to checkpoint immunotherapy even in the brain likely resulting from its elevated neoantigen burden., Conclusions: These syngeneic QPP models of glioblastoma demonstrate clinically relevant profiles of immunotherapeutic sensitivity and potential utility for both mechanistic discovery and evaluation of immune therapies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 ( PVT1 ) was triggered by the tumor cell-produced interleukin-6. Mechanistically, PVT1 modulated RAF proto-oncogene serine/threonine protein kinase-mediated phosphorylation of tryptophan 2,3-dioxygenase in TASc, facilitating its enzymatic activities in catalysis of tryptophan to kynurenine. Depletion of TASc-expressed PVT1 suppressed PDAC tumor growth. Furthermore, depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance.

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis all exhibited down-regulation of MANF (mesencephalic astrocyte-derived neurotrophic factor) and HSPA5 (heat shock 70-kDa protein 5) in the heart; this down-regulation was particularly notable in female mice. ICI myocarditis was amplified by heart-specific genetic deletion of mouse Manf and was attenuated by administration of recombinant MANF protein, suggesting a causal role. Ironically, both MANF and HSPA5 were transcriptionally induced by liganded estrogen receptor β and inhibited by androgen receptor. However, ICI treatment reduced serum estradiol concentration to a greater extent in female compared to male mice. Treatment with an estrogen receptor β-specific agonist and androgen depletion therapy attenuated ICI-associated cardiac effects. Together, our data suggest that ICI treatment inhibits estradiol-dependent expression of MANF/HSPA5 in the heart, curtailing the cardiomyocyte response to immune injury. This endocrine-cardiac-immune pathway offers new insights into the mechanisms of sex differences in cardiac disease and may offer treatment strategies for ICI myocarditis.

Many emerging adults have experienced increased financial distress and mental health problems during the COVID-19 pandemic, and isolation may have amplified the importance of close relationships (especially as parents' influence diminishes during this developmental stage). Using the ABC-X Model to frame our model, we tested whether financial distress (C) mediates the associations between COVID-19 impact (A) and anxiety and depressive symptoms (X), and whether or not romantic relationship quality (B) moderates these indirect associations. Our sample comprised of 1950 U.S. emerging adults in a romantic relationship. Mediation and first-stage moderated mediation were tested using structural equation modeling. Financial distress partially mediated the association between COVID-19 impact and anxiety symptoms and fully mediated the association between COVID-19 impact and depressive symptoms. Strong evidence of moderated mediation was found but in the opposite direction expected: the indirect associations of COVID-19 impact with anxiety and depressive symptoms (through financial distress) were stronger for those in high-quality romantic relationships. The findings may inform policy and practice aimed at optimizing the mental health of emerging adults, especially in light of the ongoing COVID-19 pandemic: specifically, alleviating financial distress may improve the mental health of emerging adults, while focusing on the quality of their romantic relationships may not.

Median survival of patients with glioblastoma (GBM) treated with standard of care which consists of maximal safe resection of the contrast-enhancing portion of the tumor followed by radiation therapy with concomitant adjuvant temozolomide (TMZ) remains 15 months. The tumor microenvironment (TME) is known to contain immune suppressive myeloid cells with minimal effector T cell infiltration. Stimulator of interferon genes (STING) is an important activator of immune response and results in production of Type 1 interferon and antigen presentation by myeloid cells. This review will discuss important developments in STING agonists, potential biomarkers for STING response, and new combinatorial therapeutic approaches in gliomas., Competing Interests: Competing interests: ABH has licensed intellectual property that has generated royalty income from Celldex Therapeutics and DNAtrix, serves on the advisory boards of WCG Oncology and Caris Life Sciences, receives research support from AbbVie, Moleculin, Celularity, Codiak Biosciences, and received consulting fees from Novocure and Istari Oncology. A.H.S. is shareholder of Exicure Inc., which develops the Spherical Nucleic Acid (SNA) therapeutic platforms. A.H.S. is inventor on patent US20150031745A1, which describes SNA nanoconjugates to cross the BBB, and on provisional patent 30938/2021-221P, describing SNAs to target the cGAS-STING pathway. DMA serves on the advisory boards of Diverse Bio Pharma, Immunogenesis, MAIA Biotech Inc., Jackson Laboratory. The rest of the authors declare no potential conflict of interest., (Copyright: © 2022 Tripathi S et al.)

A theoretically grounded, validated measure of parent financial socialization is needed. This article describes the development and validation process of three new scales: the Parent Financial Modeling Scale (eight items), the Parent-Child Financial Discussion Scale (nine items), and the Experiential Learning of Finances Scale (three items). These may be treated as subscales of a multidimensional latent construct: the Parent Financial Socialization Scale (20 items). The three scales measure the three primary methods of family financial socialization. The scales are designed to be retrospective, with target participants being U.S. emerging adults (age 18-30). A rigorous development process was undertaken: an initial pool of items was generated, expert assessments were collected, cognitive interviews were conducted, and (following preliminary data collection) preliminary item reduction analysis and confirmatory factor analysis (CFA) were conducted. Final data were collected from a diverse (51.7% female, 47.6% male; 31.6% White, 22.0% Black, 19.8% Latinx, 14.6% Asian; 50.4% no parent with college degree, 47.4% parent with college degree) sample of 4,182 U.S. emerging adults. During validation, item reduction analysis, CFA, reliability tests, measurement invariance tests, and construct validity tests were conducted. The scales demonstrated acceptable reliability and validity, and invariance was established across sex, race, and parents' education level. These scales are unique in their ability to capture nuance and will allow for comparisons across studies. They will enhance the quality of family financial socialization research, expand the questions that can be answered, and allow for the development of programming that is effective for a wide range of families. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Profound environmental changes will affect vast human populations, if not pose an existential threat to humanity, raising the question how individuals will adapt psychologically to address these changes and how they manage stress and anxiety in the face of chronic threats such as climate change. We propose that ecological coping (efforts to manage adaptational demands of a degrading environment) is an important construct. Our purpose is to use a person-centered approach to identify profiles of ecological coping and to determine how these profiles differ on mental health outcomes and pro-environmental behaviors in an online survey (N = 334 U.S. adults). Using Latent Profile Analysis (LPA), we also investigate whether these profiles are explained based on general (demographics) or environment-specific (e.g., eco-stressors) factors. Results showed: (1) The identification of two profiles: Adaptive Approach Coping (P1; 69.46%) and Maladaptive Avoidance Coping (P2; 30.54%); (2) Environment-related factors (vs. health) are associated with the profiles; (3) All 6 environment-specific characteristics predicted profile membership. Future research and policy can use these profiles to develop interventions to increase pro-environmental engagement to address climate change.

Therapeutic monoclonal antibodies directed against PD-L1 (e.g., atezolizumab) disrupt PD-L1:PD-1 signaling and reactivate exhausted cytotoxic T-cells in the tumor compartment. Although anti-PD-L1 antibodies are successful as immune checkpoint inhibitor (ICI) therapeutics, there is still a pressing need to develop high-affinity, low-molecular-weight ligands for molecular imaging and diagnostic applications. Affibodies are small polypeptides (∼60 amino acids) that provide a stable molecular scaffold from which to evolve high-affinity ligands. Despite its proven utility in the development of imaging probes, this scaffold has never been optimized for use in mRNA display, a powerful in vitro selection platform incorporating high library diversity, unnatural amino acids, and chemical modification. In this manuscript, we describe the selection of a PD-L1-binding affibody by mRNA display. Following randomization of the 13 amino acids that define the binding interface of the well-described Her2 affibody, the resulting library was selected against recombinant human PD-L1 (hPD-L1). After four rounds, the enriched library was split and selected against either hPD-L1 or the mouse ortholog (mPD-L1). The dual target selection resulted in the identification of a human/mouse cross-reactive PD-L1 affibody (M1) with low nanomolar affinity for both targets. The M1 affibody bound with similar affinity to mPD-L1 and hPD-L1 expressed on the cell surface and inhibited signaling through the PD-L1:PD-1 axis at low micromolar concentrations in a cell-based functional assay. In vivo optical imaging with M1-Cy5 in an immune-competent mouse model of lymphoma revealed significant tumor uptake relative to a Cy5-conjugated Her2 affibody.

Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti-PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti-PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti-PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.

Accumulating evidence has been found for the associations from sexual minority stressors to intimate partner violence (IPV) among same-sex couples. Yet key gaps still exist, including the rare utilization of couple dyadic data, the understudied moderating and mediating mechanisms, and the few studies conducted during the transitional period of same-sex marriage legalization. To address these gaps, we used cross-sectional, dyadic data collected from 144 US same-sex couples during the 2014-2015 national campaign for the legalization of same-sex marriage. Guided by the systemic transactional model (STM), we examined associations from sexual minority stressors (including both internalized homophobia and discrimination) to same-sex IPV and tested whether commitment moderated or mediated these associations. Overall, we found evidence supporting the STM: (1) High internalized homophobia and discrimination were related to high prevalence and/or frequency of IPV perpetration; (2) high commitment attenuated positive associations between high discrimination and high prevalence and/or frequency of IPV perpetration; and (3) high internalized homophobia was related to low commitment, which in turn was related to high prevalence and/or frequency of IPV perpetration. Collectively, our study identified commitment as both a moderator and mediator in associations from sexual minority stressors to same-sex IPV. Further, the roles of commitment (i.e., moderator or mediator) depend on whether the focal sexual minority stressors are distal and more intermittent (i.e., heterosexist discrimination) or proximal and more constant (i.e., internalized homophobia)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The combination of ISA101, a human papilloma virus (HPV) 16 peptide vaccine, and nivolumab showed a promising response rate of 33% in patients with incurable HPV-16 + cancer. Here we report long-term clinical outcomes and immune correlates of response., Methods: Patients with advanced HPV-16 + cancer and less than two prior regimens for recurrence were enrolled to receive ISA101 (100 µg/peptide) on days 1, 22, and 50 and nivolumab 3 mg/kg every 2 weeks beginning day 8 for up to 1 year. Baseline tumor samples were stained with multiplex immunofluorescence for programmed death-ligand 1 (PD-L1), programmed cell death protein-1 (PD-1), CD3, CD8, CD68, and pan-cytokeratin in a single panel and scanned with the Vectra 3.0 multispectral microscope. Whole transcriptome analysis of baseline tumors was performed with Affymetrix Clariom D arrays. Differential gene expression analysis was performed on responders versus non-responders., Results: Twenty-four patients were followed for a median of 46.5 months (95% CI, 46.0 months to not reached (NR)). The median duration of response was 11.2 months (95% CI, 8.51 months to NR); three out of eight (38%) patients with objective response were without progression at 3 years. The median and 3-year overall survival were 15.3 months (95% CI, 10.6 months to 27.2 months) and 12.5% (95% CI, 4.3% to 36%), respectively. The scores for activated T cells ((CD3 + PD-1 + )+(CD3 + CD8 + PD-1 + )), activated cytotoxic T cells (CD3 + CD8 + PD-1 + ), and total macrophage ((CD68 + PD-L1 - )+(CD68 + PD-L1 + )) in tumor were directly correlated with clinical response (p<0.05) and depth of response with the two complete response patients having the highest degree of CD8 + T cells. Gene expression analysis revealed differential regulation of 357 genes (≥1.25 fold) in non-responders versus responders (p<0.05). Higher expression of immune response, inflammatory response and interferon-signaling pathway genes were correlated with clinical response (p<0.05)., Conclusions: Efficacy of ISA101 and nivolumab remains promising in long-term follow-up. Increased infiltration by PD-1 + T cells and macrophages was predictive of response. Enrichment in gene sets associated with interferon-γ response and immune infiltration strongly predicted response to therapy. A randomized trial is ongoing to test this strategy and to further explore correlates of immune response with combined nivolumab and ISA101, versus nivolumab alone., Trial Registration Number: NCT02426892., Competing Interests: Competing interests: RF: reports personal fees from Regeneron-Sanofi, Ayala Pharmaceuticals, Klus Pharma, Bicara Therapeutics, Medscape, Carevive systems, G1 Therapeutics, Prelude Therapeutics, Merck, and Intellisphere in the past 36 months outside of the submitted work; and institutional fees from AstraZeneca, Merck, Genentech, Pfizer, Rakuten, Nanobiotix, and EMD Serono in the past 36 months. WW has received honoraria/speaker’s fees and/or participated in advisory boards from Roche/Genentech, Bristol Myers Squibb, Eli Lilly, Merck, AstraZeneca, Pfizer, Takeda, Janssen, Boehringer Ingelheim, Novartis, Sanofi Aventis. CJMM is Chief Scientific Officer of ISA Pharmaceuticals, a biotech company aiming at registration of a long peptide vaccine very similar to the one studied in this manuscript. MAC reports grants and personal fees from ImmunoGenesis, Inc. and ImmunoMet, Inc., personal fees from Alligator Bioscience, Inc., ImmunOS, Inc., Oncoresponse, Inc., Pieris, Inc., Nurix, Inc., Aptevo, Inc., Servier, Inc., Kineta, Inc., Salarius, Inc., Xencor, Inc., Agenus, Inc., Mereo, Inc., Astrazeneca, Inc., Amunix, Inc., Adagene, Inc., outside the submitted work; In addition, Dr. Curran has a patent Methods and Composition for Localized Secretion of Anti-CTLA-4 Antibodies with royalties paid by multiple licensees, a patent Dual specificity antibodies which bind both PD-L1 and PD-L2 and prevent their binding to PD-1 with royalties paid by ImmunoGenesis, Inc. IIW reports consults fees from ROCHE, Bayer, BMS, Astra Zeneca, Pfizer, HTG molecular, Merck, ClaxoSmithKline, Guardant Health, Novartis, Flame, Sanofi, Janssen, Daiichi Sankyo, Oncocyte, Amgen, MSD, Medcape; honoraria from Medscape, Roche, Pfizer, AstraZeneca, Platform Health, Merck; and Grants from Genetech, HTG Molecular, Merck, BMS, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis, Akova. JJL reports he received grant from Cancer Center Support Grant (CCSG) P30 CA016672 from National Cancer Institute. BG reports consult fees from Regeneron and grants from Pfizer Inc, ISA Pharmaceuticals, and Medimmune., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In order to fuel their relentless expansion, cancers must expand their vasculature to augment delivery of oxygen and essential nutrients. The disordered web of irregular vessels that results, however, leaves gaps in oxygen delivery that foster tumor hypoxia. At the same time, tumor cells increase their oxidative metabolism to cope with the energetic demands of proliferation, which further worsens hypoxia due to heightened oxygen consumption. In these hypoxic, nutrient-deprived environments, tumors and suppressive stroma evolve to flourish while antitumor immunity collapses due to a combination of energetic deprivation, toxic metabolites, acidification, and other suppressive signals. Reversal of cancer hypoxia thus has the potential to increase the survival and effector function of tumor-infiltrating T cells, as well as to resensitize tumors to immunotherapy. Early clinical trials combining hypoxia reduction with immune checkpoint blockade have shown promising results in treating patients with advanced, metastatic, and therapeutically refractory cancers.

Despite our wealth, child poverty in the United States remains too high. The social safety net prevents and mitigates poverty for millions of children each year and evidence demonstrates long-term positive effects for recipients. But absent a commitment to universalism, our public investments in children produce uneven - and often inequitable - results. Our current system is heavily means-tested and work-conditioned. Though heavily targeted, it varies widely in adequacy and coverage by location and across population groups and it fails to serve all children in need. This article describes the evolution of the US social safety net for children over the last century. It traces the early 20th century origins of the contemporary system and the changes it saw through the mid-century's War on Poverty expansions and late 20th century's welfare reforms. Focusing specifically on federal cash and near-cash programs, it discusses key facets and principles of the current social safety net structure, its impact on children's health and economic well-being, remaining gaps, and promising advances for the future. Temporary improvements to the social safety net enacted as part of the pandemic response indicate important ways in which our public supports can reach more families, more consistently, moving forward. To reduce child poverty, one of the most promising approaches is to enact a national child allowance in the United States. Converting the existing Child Tax Credit into a universal child allowance, making it more generous, and delivering it to families on a regular basis throughout the year can accomplish this goal., (Copyright © 2021 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Purpose: Activation of STING ( s timulator of in terferon g enes) can trigger a robust, innate antitumor immune response in immunologically "cold" tumors such as glioblastoma., Patients and Methods: A small-molecule STING agonist, IACS-8779, was stereotactically administered using intraoperative navigation intratumorally in dogs with spontaneously arising glioblastoma. The phase I trial used an escalating dose design, ascending through four dose levels (5-20 μg). Treatment was repeated every 4-6 weeks for a minimum of two cycles. Radiographic response to treatment was determined by response assessment in neuro-oncology (RANO) criteria applied to isovoxel postcontrast T1-weighted MR images obtained on a single 3T magnet., Results: Six dogs were enrolled and completed ≥1 cycle of treatment. One dog was determined to have an abscess and was removed from further analysis. One procedure-related fatality was observed. Radiographic responses were dose dependent after the first cycle. The first subject had progressive disease, whereas there was 25% volumetric reduction in one subject and greater than 50% in the remaining surviving subjects. The median progression-free survival time was 14 weeks (range: 0-22 weeks), and the median overall survival time was 32 weeks (range: 11-39 weeks)., Conclusions: Intratumoral STING agonist (IACS-8779) administration was well tolerated in dogs with glioblastoma to a dose of 15 μg. Higher doses of IACS-8779 were associated with radiographic responses., (©2021 The Authors; Published by the American Association for Cancer Research.)

Un Abrazo Para La Familia™ (Abrazo) is a 3-h modular preventive intervention designed for low-income caregivers who are co-survivors of cancer. Here we (1) consider the benefit to survivors of cancer, that is, the care recipients who participate in Abrazo; (2) summarize the literature specific to research outreach to low-income, underserved populations when they are faced with cancer; and (3) describe current steps being taken in Southern Arizona to reach these populations via Abrazo. Specific to considering the benefit to care recipients, we analyzed care recipient data derived from three existing cohorts of Abrazo participants. Analyses of the combined cohorts of these data demonstrate that Abrazo is effective with care recipients given statistically significant higher cancer knowledge and self-efficacy scores, pre- vs. post-intervention. We can now report benefit to care recipients who participate in Abrazo. This allows us, with confidence, to expand research recruitment efforts to include care recipients as part of the Abrazo intervention in our efforts to serve low-income, underserved populations when faced with cancer., (© 2020. American Association for Cancer Education.)

Immune checkpoint blocking antibodies are a cornerstone in cancer treatment; however, they benefit only a subset of patients and biomarkers to guide immune checkpoint blockade (ICB) treatment choices are lacking. We designed this study to identify blood-based correlates of clinical outcome in ICB-treated patients. We performed immune profiling of 188 ICB-treated patients with melanoma using multiparametric flow cytometry to characterize immune cells in pretreatment peripheral blood. A supervised statistical learning approach was applied to a discovery cohort to classify phenotypes and determine their association with survival and treatment response. We identified three distinct immune phenotypes (immunotypes), defined in part by the presence of a LAG-3 + CD8 + T cell population. Patients with melanoma with a LAG + immunotype had poorer outcomes after ICB with a median survival of 22.2 months compared to 75.8 months for those with the LAG - immunotype ( P = 0.031). An independent cohort of 94 ICB-treated patients with urothelial carcinoma was used for validation where LAG + immunotype was significantly associated with response ( P = 0.007), survival ( P < 0.001), and progression-free survival ( P = 0.004). Multivariate Cox regression and stratified analyses further showed that the LAG + immunotype was an independent marker of outcome when compared to known clinical prognostic markers and previously described markers for the clinical activity of ICB, PD-L1, and tumor mutation burden. The pretreatment peripheral blood LAG + immunotype detects patients who are less likely to benefit from ICB and suggests a strategy for identifying actionable immune targets for further investigation., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Intratumoral injection of cyclic dinucleotide (CDN) agonists of the stimulator of interferon genes (STING) pathway engages innate immune activation and priming of adaptive immune effectors to foster local and distal tumor clearance. Despite proven therapeutic efficacy in preclinical models, a thorough understanding of how CDNs reprogram suppressive myeloid stroma in mouse and man is lacking., Methods: Here, we perform deep transcript-level and protein-level profiling of myeloid-derived suppressor cells and M2 macrophages following stimulation with CDNs of ascending potency. Additionally, we leverage orthotopic Kras +/G12D TP53 +/R172H Pdx1-Cre (KPC) derived models of pancreatic adenocarcinoma (PDAC) to determine the capacity for locally administered CDNs to sensitize PDAC to immune checkpoint blockade. We use bioluminescent in vivo imaging and 30-parameter flow cytometry to profile growth kinetics and remodeling of the tumor stroma post-therapy., Results: Highly potent synthetic STING agonists repolarize suppressive myeloid populations of human and murine origin in part through inhibition of Myc signaling, metabolic modulation, and antagonism of cell cycle. Surprisingly, high-potency synthetic agonists engage qualitatively unique pathways as compared with natural CDNs. Consistent with our mechanistic observations, we find that intratumoral injection of the highest activity STING agonist, IACS-8803, into orthotopic pancreatic adenocarcinoma lesions unmasks sensitivity to checkpoint blockade immunotherapy. Dimensionality reduction analyses of high parameter flow cytometry data reveals substantial contributions of both myeloid repolarization and T cell activation underlying the in vivo therapeutic benefit of this approach., Conclusions: This study defines the molecular basis of STING-mediated myeloid reprogramming, revealing previously unappreciated and qualitatively unique pathways engaged by CDNs of ascending potency during functional repolarization. Furthermore, we demonstrate the potential for high potency CDNs to overcome immunotherapy resistance in an orthotopic, multifocal model of PDAC., Competing Interests: Competing interests: MAC reports personal fees from ImmunoGenesis, Inc, personal fees from Alligator Bioscience, Inc, personal fees from ImmunOS, Inc, grants and personal fees from ImmunoMet, Inc, personal fees from Oncoresponse, Inc, personal fees from Pieris, Inc, personal fees from Nurix, Inc, personal fees from Aptevo, Inc, personal fees from Servier, Inc, personal fees from Kineta, Inc, personal fees from Salarius, Inc, personal fees from Xencor, Inc, personal fees from Agenus, Inc, personal fees from Mereo, outside the submitted work; in addition, MAC has a patent 'Methods and Composition for Localized Secretion of Anti-CTLA-4 Antibodies' licensed to multiple licensees, and a patent 'Dual specificity antibodies which bind both PD-L1 and PD-L2 and prevent their binding to PD-1' licensed to ImmunoGenesis, Inc. MAC, MEDF and PJ have a patent 'Cyclic Dinucleotides as Agonists of Stimulator of Interferon Gene Dependent Signaling' licensed to ImmunoGenesis, Inc., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The blood-brain barrier (BBB) inhibits adequate dosing/penetration of therapeutic agents to malignancies in the brain. Low-intensity pulsed ultrasound (LIPU) is a safe therapeutic method of temporary BBB disruption (BBBD) to enhance chemotherapeutic delivery to the tumor and surrounding brain parenchyma for treatment of glioblastoma., Experimental Design: We investigated if LIPU could enhance therapeutic efficacy of anti-PD-1 in C57BL/6 mice bearing intracranial GL261 gliomas, epidermal growth factor receptor variant III (EGFRvIII) chimeric antigen receptor (CAR) T cells in NSG mice with EGFRvIII-U87 gliomas, and a genetically engineered antigen-presenting cell (APC)-based therapy producing the T-cell attracting chemokine CXCL10 in the GL261-bearing mice., Results: Mice treated with anti-PD-1 and LIPU-induced BBBD had a median survival duration of 58 days compared with 39 days for mice treated with anti-PD-1, and long-term survivors all remained alive after contralateral hemisphere rechallenge. CAR T-cell administration with LIPU-induced BBBD resulted in significant increases in CAR T-cell delivery to the CNS after 24 ( P < 0.005) and 72 ( P < 0.001) hours and increased median survival by greater than 129%, in comparison with CAR T cells alone. Local deposition of CXCL10-secreting APCs in the glioma microenvironment with LIPU enhanced T-cell glioma infiltration during the therapeutic window ( P = 0.004) and markedly enhanced survival ( P < 0.05)., Conclusions: LIPU increases immune therapeutic delivery to the tumor microenvironment with an associated increase in survival and is an emerging technique for enhancing novel therapies in the brain., (©2021 The Authors; Published by the American Association for Cancer Research.)

Harnessing the immune system to treat cancer through inhibitors of CTLA4 and PD-L1 has revolutionized the landscape of cancer. Rational combination strategies aim to enhance the antitumor effects of immunotherapies, but require a deep understanding of the mechanistic underpinnings of the immune system and robust preclinical and clinical drug development strategies. We review the current approved immunotherapy combinations, before discussing promising combinatorial approaches in clinical trials and detailing innovative preclinical model systems being used to develop rational combinations. We also discuss the promise of high-order immunotherapy combinations, as well as novel biomarker and combinatorial trial strategies. SIGNIFICANCE: Although immune-checkpoint inhibitors are approved as dual checkpoint strategies, and in combination with cytotoxic chemotherapy and angiogenesis inhibitors for multiple cancers, patient benefit remains limited. Innovative approaches are required to guide the development of novel immunotherapy combinations, ranging from improvements in preclinical tumor model systems to biomarker-driven trial strategies., (©2021 American Association for Cancer Research.)

Purpose: As hypoxia can mediate resistance to immunotherapy, we investigated the safety, tolerability, and efficacy of combining evofosfamide, a prodrug that alleviates hypoxia, with ipilimumab, an immune checkpoint inhibitor, in immunologically "cold" cancers, which are intrinsically insensitive to immunotherapy, as well as in "hot/warm" metastatic cancers that are, atypical of such cancers, resistant to immunotherapy., Patients and Methods: In a phase I, 3+3 dose-escalation trial (NCT03098160), evofosfamide (400-640 mg/m 2 ) and ipilimumab (3 mg/kg) were administered in four 3-week cycles. The former was administered on days 1 and 8 of cycles 1-2, while the latter was administered on day 8 of cycles 1-4. Response was assessed using immune-related RECIST and retreatment was allowed, if deemed beneficial, after completion of cycle 4 or at progression., Results: Twenty-two patients were enrolled, of whom 21 were evaluable, encompassing castration-resistant prostate cancer ( n = 11), pancreatic cancer ( n = 7), immunotherapy-resistant melanoma ( n = 2), and human papillomavirus-negative head and neck cancer ( n = 1). Drug-related hematologic toxicities, rash, fever, nausea, vomiting, and elevation of liver enzymes were observed in > 10% of patients. The most common drug-related grade 3 adverse event was alanine aminotransferase elevation (33.3%). Two patients discontinued ipilimumab and 4 required evofosfamide deescalation due to toxicity. Of 18 patients with measurable disease at baseline, 3 (16.7%) achieved partial response and 12 (66.7%) achieved stable disease. The best responses were observed at 560 mg/m 2 evofosfamide. Preexisting immune gene signatures predicted response to therapy, while hypermetabolic tumors predicted progression. Responders also showed improved peripheral T-cell proliferation and increased intratumoral T-cell infiltration into hypoxia., Conclusions: No new or unexpected safety signals were observed from combining evofosfamide and ipilimumab, and evidence of therapeutic activity was noted., (©2021 American Association for Cancer Research.)

Following from an adapted family stress model (FSM), we used two-wave, secondary data from the Building Strong Families project, focusing on 4,424 primarily lower-income, unmarried couples expecting their first child together. We used cross-lagged analyses to test the directionality of the associations among financial difficulties, depressive symptoms, destructive interparental conflict, and coparenting alliance for both fathers and mothers when children were 15 and 36 months old. Two of the three hypotheses provided support for the FSM. First, destructive conflict predicted coparenting alliance (but not the reverse). Specifically, higher destructive conflict at 15 months for both fathers and mothers predicted lower coparenting alliance at 36 months for both fathers and mothers. Second, depressive symptoms predicted destructive conflict (but not the reverse). Specifically, fathers' (but not mothers') higher depressive symptoms at 15 months predicted both their own and mothers' higher destructive conflict at 36 months. Contrary to predictions, financial difficulties did not predict depressive symptoms; instead, we found support for the reverse: For mothers only, higher depressive symptoms at 15 months predicted higher financial difficulties at 36 months. Collectively, the results support the use of the FSM to understand the directionality of associations among key risk factors, especially depressive symptoms and destructive conflict, for primarily lower-income, unmarried couples expecting their first child together. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Heteronormativity, as defined in queer theory, is the presumption and privileging of heterosexuality. Research on how young people make sense of and narrate heteronormativity in their own lives is needed to inform theories of heteronormativity. Using queer and intersectional frameworks, we conducted semi-structured interviews with 14 sexual and gender minority young people (ages 18 to 24), analyzed using thematic analysis, to examine how young adults make sense of heteronormativity. Participants discussed how gender expression informed both sexuality and sexual attraction. Participants prioritized biological parenthood over other family constructions but rarely discussed marriage. Gender, sexuality, and race contributed important contexts for how participants described heteronormativity in their lives and should be the focus of future research. Finally, binaries of gender, sexuality, and family intersected in participants' lives and their narrative constructions.

More than one-third of US children live in families with three or more children. The contemporary impact of larger family size on children's family resources remains an under-explored point of inequity. Larger family size is not only more common among Black and Hispanic children, but Black and Hispanic children in larger families (Black children, especially so) face higher poverty risks relative to White children in larger families. This analysis uses children's number of siblings and children's race and ethnicity to chart the intersectional aspects of disparity in the risk and incidence of poverty and the anti-poverty effects of large federal cash supports, the Earned Income Tax Credit and Child Tax Credit. It draws upon 2014-2017 Current Population Survey data and the NBER TAXSIM calculator to apply 2018 tax law, inclusive of the Tax Cuts and Jobs Act of 2017. It reveals well-documented disparities in poverty rates and benefit access and receipt experienced by children of color are further exacerbated by policy structures that discriminate against an under-acknowledged aspect of children's family life: their family size. Racial bias in policy design that sees tax credit access mechanisms and earnings and benefit structures disproportionately exclude that Black and Hispanic children also disproportionately exclude Black and Hispanic children by their family size. Without reforms that tackle both inequities, policy action that closes the poverty gap between larger and smaller families will see the racial gap in child poverty remain., Competing Interests: Conflict of interestNot applicable, (© Springer Science+Business Media, LLC, part of Springer Nature 2021.)

Immune checkpoint blockade (ICB) has demonstrated an impressive outcome in patients with metastatic melanoma, yet, durable complete response; even with Ipilimumab/Nivolumab combo are under 30%. Primary and acquired resistance in response to ICB is commonly due to a tumor immune escape mechanism dictated by the tumor microenvironment (TME). Macrophage Migratory Inhibition Factor (MIF) has emerged as an immunosuppressive factor secreted in the TME. We have previously demonstrated that blockade of the MIF-CD74 signaling on macrophages and dendritic cells restored the anti-tumor immune response against melanoma. Here, we report that inhibition of the MIF-CD74 axis combined with ipilimumab could render resistant melanoma to better respond to anti-CTLA-4 treatment. We provide evidence that blocking the MIF-CD74 signaling potentiates CD8+ T-cells infiltration and drives pro-inflammatory M1 conversion of macrophages in the TME. Furthermore, MIF inhibition resulted in reprogramming the metabolic pathway by reducing lactate production, HIF-1α and PD-L1 expression in the resistant melanoma cells. Melanoma patient data extracted from the TCGA database supports the hypothesis that high MIF expression strongly correlates with poor response to ICB therapy. Our findings provide a rationale for combining anti-CTLA-4 with MIF inhibitors as a potential strategy to overcome resistance to ICB therapy in melanoma, turning a "cold" tumor into a "hot" one mediated by the activation of innate immunity and reprogramming of tumor metabolism and reduced PD-L1 expression in melanoma cells., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Despite the clinical success of T-cell checkpoint blockade, most patients with cancer still fail to have durable responses to immunotherapy. The molecular mechanisms driving checkpoint blockade resistance, whether preexisting or evolved, remain unclear. To address this critical knowledge gap, we treated B16 melanoma with the combination of CTLA-4, PD-1, and PD-L1 blockade and a Flt3 ligand vaccine (≥75% curative), isolated tumors resistant to therapy, and serially passaged them in vivo with the same treatment regimen until they developed complete resistance. Using gene expression analysis and immunogenomics, we determined the adaptations associated with this resistance phenotype. Checkpoint resistance coincided with acquisition of a "hypermetabolic" phenotype characterized by coordinated upregulation of the glycolytic, oxidoreductase, and mitochondrial oxidative phosphorylation pathways. These resistant tumors flourished under hypoxic conditions, whereas metabolically starved T cells lost glycolytic potential, effector function, and the ability to expand in response to immunotherapy. Furthermore, we found that checkpoint-resistant versus -sensitive tumors could be separated by noninvasive MRI imaging based solely on their metabolic state. In a cohort of patients with melanoma resistant to both CTLA-4 and PD-1 blockade, we observed upregulation of pathways indicative of a similar hypermetabolic state. Together, these data indicated that melanoma can evade T-cell checkpoint blockade immunotherapy by adapting a hypermetabolic phenotype., (©2020 American Association for Cancer Research.)

We present a new simple and efficient method for correlation of unevenly and differently sampled data. This new method overcomes problems with other methods for correlation with non-uniform sampling and is an easy modification to existing correlation based codes. To demonstrate the usefulness of this new method to real-world examples, we apply the method with good success to two glaciological examples to map the ages from a well-dated ice core to a nearby core, and by tracing isochronous layers within the ice sheet measured from ice-penetrating radar between the two ice core sites.

Advances in our understanding of tumor immune biology and development of cancer immunotherapies have led to improved outcomes for patients that suffer from aggressive cancers such as metastatic melanoma. Despite these advances, a significant proportion of patients still fail to benefit, and as a result, attention has shifted to understanding how cancer cells escape immune destruction. Of particular interest is the metabolic landscape of the tumor microenvironment, as recent studies have demonstrated how both competition for essential nutrients and depletion of specific amino acids can promote T cell dysfunction. Here, we will discuss the major energetic pathways engaged by both T cells and cancer cells, metabolic substrates present in the tumor microenvironment, and emerging therapeutic strategies that seek to improve T cell metabolic fitness and bolster the antitumor immune response., Competing Interests: Declaration of Competing Interest MAC is the founder and president of ImmunoGenesis, Inc. AL declared no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In order to prioritize available immune therapeutics, immune profiling across glioma grades was conducted, followed by preclinical determinations of therapeutic effect in immune-competent mice harboring gliomas. T cells and myeloid cells were isolated from the blood of healthy donors and the blood and tumors from patients with glioma and profiled for the expression of immunomodulatory targets with an available therapeutic. Murine glioma models were used to assess therapeutic efficacy of agents targeting the most frequently expressed immune targets. In patients with glioma, the A2aR/CD73/CD39 pathway was most frequently expressed, followed by the PD-1 pathway. CD73 expression was upregulated on immune cells by 2-hydroxyglutarate in IDH1 mutant glioma patients. In murine glioma models, adenosine receptor inhibitors demonstrated a modest therapeutic response; however, the addition of other inhibitors of the adenosine pathway did not further enhance this therapeutic effect. Although adenosine receptor inhibitors could recover immunological effector functions in T cells, immune recovery was impaired in the presence of gliomas, indicating that irreversible immune exhaustion limits the effectiveness of adenosine pathway inhibitors in patients with glioma. This study illustrates vetting steps that should be considered before clinical trial implementation for immunotherapy-resistant cancers, including testing an agent's ability to restore immunological function in the context of intended use.

Programmed death ligand 1 (PD-L1) is a critical immune checkpoint ligand whose overexpression on tumor cells provides a mechanism of escape from immune surveillance. The interaction between PD-L1 and PD-1 on T cell lymphocytes suppresses both T cell activation and effector function and is engaged by cancers to dampen antitumor immunity. Here, we used mRNA display to engineer an 18-residue linear peptide that binds to human PD-L1. This peptide, which we term SPAM (signal peptide-based affinity maturated ligand), is nonhomologous to known PD-L1 binding peptides and mAbs, with dissociation constants ( K D ) of 119 and 67 nM for unglycosylated and glycosylated human PD-L1, respectively. The SPAM peptide is highly selective for human PD-L1 and shows no significant binding to either mouse PD-L1 or human PD-L2. Competition binding assays indicate that the SPAM peptide binding site overlaps with the binding site of PD-1 as well as therapeutic anti-PD-L1 antibodies. Taken together, these results suggest that the SPAM peptide specifically binds to human PD-L1 and could potentially serve as a PD-L1 affinity agent and PD-L1/PD-1 pathway modulator.

Guided by the spillover hypothesis of family systems theory, we used data from the Building Strong Families project to examine intrafamily relations between destructive and constructive interparental conflict, harsh and supportive parenting behaviors, and coparenting alliance across different family configurations: married, cohabiting, and noncohabiting (never married) parents. Our sample ( N = 2,784 couples/parents) was racially diverse, low-income couples/parents who were unmarried at the conception of their child. All variables were measured when children were approximately 36 months of age. Interparental conflict was assessed through an instrument that included both parents' reported conflict in the relationship and the perception of the other parent's conflict behaviors. Parenting behaviors were measured through observational data and coparenting alliance was based on mothers' and fathers' reports. As expected, path analyses revealed that destructive interparental conflict was related to lower levels of coparenting alliance, whereas constructive interparental conflict was related to higher levels of coparenting alliance, for mothers and fathers. For fathers only, destructive interparental conflict related to harsh parenting, suggesting that paternal parenting is vulnerable to the quality of the relationship with the mother. None of the proposed associations differed by family structure. These findings suggest the need for intervention programs to focus on promoting adaptive conflict management behaviors rather than on family structure. (PsycInfo Database Record (c) 2020 APA, all rights reserved).