Publications by authors named "Rakesh K Jain"

481 Publications

Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy.

Proc Natl Acad Sci U S A 2021 Nov;118(45)

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;

Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair-proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.
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http://dx.doi.org/10.1073/pnas.2105323118DOI Listing
November 2021

Losartan prevents tumor-induced hearing loss and augments radiation efficacy in NF2 schwannoma rodent models.

Sci Transl Med 2021 07;13(602)

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Hearing loss is one of the most common symptoms of neurofibromatosis type 2 (NF2) caused by vestibular schwannomas (VSs). Fibrosis in the VS tumor microenvironment (TME) is associated with hearing loss in patients with NF2. We hypothesized that reducing the fibrosis using losartan, an FDA-approved antihypertensive drug that blocks fibrotic and inflammatory signaling, could improve hearing. Using NF2 mouse models, we found that losartan treatment normalized the TME by (i) reducing neuroinflammatory IL-6/STAT3 signaling and preventing hearing loss, (ii) normalizing tumor vasculature and alleviating neuro-edema, and (iii) increasing oxygen delivery and enhancing efficacy of radiation therapy. In preparation to translate these exciting findings into the clinic, we used patient samples and data and demonstrated that IL-6/STAT3 signaling inversely associated with hearing function, that elevated production of tumor-derived IL-6 was associated with reduced viability of cochlear sensory cells and neurons in ex vivo organotypic cochlear cultures, and that patients receiving angiotensin receptor blockers have no progression in VS-induced hearing loss compared with patients on other or no antihypertensives based on a retrospective analysis of patients with VS and hypertension. Our study provides the rationale and critical data for a prospective clinical trial of losartan in patients with VS.
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http://dx.doi.org/10.1126/scitranslmed.abd4816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409338PMC
July 2021

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy.

Sci Immunol 2021 Jul;6(61)

Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland.

Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of T1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-γ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-γ were not toxic themselves but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways after anti-PD-1 and anti-CTLA-4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in T1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.
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http://dx.doi.org/10.1126/sciimmunol.abi7083DOI Listing
July 2021

Bevacizumab improves tumor infiltration of mature dendritic cells and effector T-cells in triple-negative breast cancer patients.

NPJ Precis Oncol 2021 Jun 29;5(1):62. Epub 2021 Jun 29.

Edwin L. Steele Laboratories, Department of Radiation Oncology Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

A single dose of bevacizumab reduced the density of angiopoietin-2-positive vessels while improving the infiltration of CD4+ T and CD8+ T cells, and mature dendritic cells in patients with primary triple-negative breast cancer. Our findings provide a rationale for including bevacizumab during neoadjuvant treatment to enhance the efficacy of immune checkpoint blockers in this disease.
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http://dx.doi.org/10.1038/s41698-021-00197-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242049PMC
June 2021

FATTY ACID SYNTHESIS IS REQUIRED FOR BREAST CANCER BRAIN METASTASIS.

Nat Cancer 2021 Apr 1;2(4):414-428. Epub 2021 Apr 1.

Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2 (HER2+) breast cancer, and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here, we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in brain. We determine that this phenotype is an adaptation to decreased lipid availability in brain relative to other tissues, resulting in a site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase (FASN) reduces HER2+ breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.
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http://dx.doi.org/10.1038/s43018-021-00183-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223728PMC
April 2021

Comparing machine learning algorithms for predicting ICU admission and mortality in COVID-19.

NPJ Digit Med 2021 May 21;4(1):87. Epub 2021 May 21.

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

As predicting the trajectory of COVID-19 is challenging, machine learning models could assist physicians in identifying high-risk individuals. This study compares the performance of 18 machine learning algorithms for predicting ICU admission and mortality among COVID-19 patients. Using COVID-19 patient data from the Mass General Brigham (MGB) Healthcare database, we developed and internally validated models using patients presenting to the Emergency Department (ED) between March-April 2020 (n = 3597) and further validated them using temporally distinct individuals who presented to the ED between May-August 2020 (n = 1711). We show that ensemble-based models perform better than other model types at predicting both 5-day ICU admission and 28-day mortality from COVID-19. CRP, LDH, and O saturation were important for ICU admission models whereas eGFR <60 ml/min/1.73 m, and neutrophil and lymphocyte percentages were the most important variables for predicting mortality. Implementing such models could help in clinical decision-making for future infectious disease outbreaks including COVID-19.
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http://dx.doi.org/10.1038/s41746-021-00456-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140139PMC
May 2021

Angiotensin Blockade Modulates the Activity of PD1/L1 Inhibitors in Metastatic Urothelial Carcinoma.

Clin Genitourin Cancer 2021 Apr 20. Epub 2021 Apr 20.

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA. Electronic address:

Background: The renin-angiotensin system is involved in the regulation of angiogenesis and cell proliferation. Angiotensin inhibition may improve drug delivery by enhancing tumor perfusion partly by downregulating transforming growth factor (TGF)-β. Because TGF-β is associated with resistance in patients with metastatic urothelial carcinoma (mUC) receiving programmed cell death protein 1/programmed cell death ligand 1 (PD1/L1) inhibitors, we hypothesized that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may enhance the outcomes of patients with mUC who receive PD1/L1 inhibitors.

Patients And Methods: Data from patients with mUC who received PD1/L1 inhibitors as monotherapy were obtained; patients from the Dana-Farber Cancer Institute constituted the discovery dataset, and data from Moffitt Cancer Center served as the validation dataset. A logistic regression investigated the impact of concurrent ACEI/ARB primarily on any regression of tumor (ART) after controlling for prognostic factors.

Results: Data were available for 178 patients from the discovery dataset, of whom 153 (86%) had received prior platinum and 33 (18.5%) concurrent ACEIs/ARBs. Multivariable logistic regression analysis revealed that ACEIs/ARBs were associated with greater probability of ART (odds ratio [OR] = 2.69; 95% confidence interval [CI], 1.15-6.30; P = .022). In the validation dataset, 101 patients were available, of whom 59 (58.4%) had received prior platinum and 22 (21.8%) concurrent ACEIs/ARBs. ACEI/ARB demonstrated a trend for association with ART (OR = 3.28; 95% CI, 0.98-10.99; P = .054) on multivariable analysis of the validation dataset.

Conclusions: Concurrent angiotensin blockade was associated with a higher rate of tumor regression in patients with mUC receiving PD1/L1 inhibitors. Validation is warranted in a prospective trial, especially given the cost efficacy of ACEIs/ARBs.
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http://dx.doi.org/10.1016/j.clgc.2021.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526625PMC
April 2021

Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas.

Nat Commun 2021 05 11;12(1):2582. Epub 2021 May 11.

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA.

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.
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http://dx.doi.org/10.1038/s41467-021-22885-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113440PMC
May 2021

Exercise Training Improves Tumor Control by Increasing CD8 T-cell Infiltration via CXCR3 Signaling and Sensitizes Breast Cancer to Immune Checkpoint Blockade.

Cancer Immunol Res 2021 07 10;9(7):765-778. Epub 2021 Apr 10.

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

The mechanisms behind the antitumor effects of exercise training (ExTr) are not fully understood. Using mouse models of established breast cancer, we examined here the causal role of CD8 T cells in the benefit acquired from ExTr in tumor control, as well as the ability of ExTr to improve immunotherapy responses. We implanted E0771, EMT6, MMTV-PyMT, and MCa-M3C breast cancer cells orthotopically in wild-type or female mice and initiated intensity-controlled ExTr sessions when tumors reached approximately 100 mm We characterized the tumor microenvironment (TME) using flow cytometry, transcriptome analysis, proteome array, ELISA, and immunohistochemistry. We used antibodies against CD8 T cells for cell depletion. Treatment with immune checkpoint blockade (ICB) consisted of anti-PD-1 alone or in combination with anti-CTLA-4. ExTr delayed tumor growth and induced vessel normalization, demonstrated by increased pericyte coverage and perfusion and by decreased hypoxia. ExTr boosted CD8 T-cell infiltration, with enhanced effector function. CD8 T-cell depletion prevented the antitumor effect of ExTr. The recruitment of CD8 T cells and the antitumor effects of ExTr were abrogated in mice, supporting the causal role of the CXCL9/CXCL11-CXCR3 pathway. ExTr also sensitized ICB-refractory breast cancers to treatment. Our results indicate that ExTr can normalize the tumor vasculature, reprogram the immune TME, and enhance the antitumor activity mediated by CD8 T cells via CXCR3, boosting ICB responses. Our findings and mechanistic insights provide a rationale for the clinical translation of ExTr to improve immunotherapy of breast cancer.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295193PMC
July 2021

Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model.

Radiat Oncol 2021 Mar 4;16(1):48. Epub 2021 Mar 4.

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 100 Blossom Street, Cox-7, Boston, MA, 02114, USA.

Background: Patients with metastatic HER2/neu-positive (HER2/neu +) breast cancer (BC) often experience treatment resistance, disease recurrences and metastases. Thus, new approaches for improving the treatment of HER2/neu + BC to prevent metastatic dissemination are urgently needed. Our previous studies have shown that losartan, an angiotensin receptor blocker, increases tumor perfusion and decreases hypoxia in a number of tumor models. Hypoxia reduces the efficacy of radiation and increases metastases. We therefore hypothesized that by modifying tumor stroma and increasing oxygenation, losartan will improve the outcome of radiotherapy and inhibit disease progression in a highly metastatic HER2/neu + murine BC model.

Methods: We established a metastatic HER2/neu + murine BC line (MCa-M3C) and used it to generate mammary fat pad isografts in syngeneic female FVB/N mice. Starting on day 3 after orthotopic tumor implantation, we administered a 7-day losartan treatment (40 mg/kg BW, gavage daily); or a 7-day losartan treatment followed by 20 Gy single dose local irradiation (S-IR) on day 10 (tumor size ~ 100 mm), or 20 Gy local fractionated (5 × 4 Gy daily) irradiation (F-IR) on days 10-14. We analyzed tumor-growth delay (TGD), development of spontaneous lung metastases, animal survival, tumor vascular density, and tumor hypoxia.

Results: Treatments with S-IR, F-IR, Losartan + S-IR, or Losartan + F-IR resulted in a significantly increased TGD (8-16 days) in MCa-M3C tumors versus controls. However, the combination of Losartan + S-IR and Losartan + F-IR further enhanced tumor response to radiation alone by increasing TGD an additional 5 to 8 days for both single and fractionated dose irradiation (P < 0.01), decreasing lung metastasis (Losartan + IR vs. Control, P < 0.025), and increasing animal survival (Losartan + IR vs. Control, P = 0.0303). In addition, losartan treatment significantly increased tumor vascularity (P = 0.0314) and decreased pimonidazole positive (hypoxic) area (P = 0.0002).

Conclusions: Combining losartan with local irradiation significantly enhanced tumor response, at least in part via reduced tumor hypoxia presumably due to increased tumor perfusion. Our findings suggest that combining losartan with radiotherapy is a potential new treatment strategy for local control and inhibiting metastasis in HER2 + BC.
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http://dx.doi.org/10.1186/s13014-021-01775-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934382PMC
March 2021

Vascular Normalization to Improve Treatment of COVID-19: Lessons from Treatment of Cancer.

Clin Cancer Res 2021 05 1;27(10):2706-2711. Epub 2021 Mar 1.

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

The dramatic impact of the COVID-19 pandemic has resulted in an "all hands on deck" approach to find new therapies to improve outcomes in this disease. In addition to causing significant respiratory pathology, infection with SARS-CoV-2 (like infection with other respiratory viruses) directly or indirectly results in abnormal vasculature, which may contribute to hypoxemia. These vascular effects cause significant morbidity and may contribute to mortality from the disease. Given that abnormal vasculature and poor oxygenation are also hallmarks of solid tumors, lessons from the treatment of cancer may help identify drugs that can be repurposed to treat COVID-19. Although the mechanisms that result in vascular abnormalities in COVID-19 are not fully understood, it is possible that there is dysregulation of many of the same angiogenic and thrombotic pathways as seen in patients with cancer. Many anticancer therapeutics, including androgen deprivation therapy (ADT) and immune checkpoint blockers (ICB), result in vascular normalization in addition to their direct effects on tumor cells. Therefore, these therapies, which have been extensively explored in clinical trials of patients with cancer, may have beneficial effects on the vasculature of patients with COVID-19. Furthermore, these drugs may have additional effects on the disease course, as some ADTs may impact viral entry, and ICBs may accelerate T-cell-mediated viral clearance. These insights from the treatment of cancer may be leveraged to abrogate the vascular pathologies found in COVID-19 and other forms of hypoxemic respiratory failure.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127351PMC
May 2021

Implications of a granulocyte-high glioblastoma microenvironment in immune suppression and therapy resistance.

J Pathol 2021 Jun 23;254(2):105-108. Epub 2021 Mar 23.

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

The failure of anti-VEGF/R and immune checkpoint therapies to improve overall survival in Phase III clinical trials in glioblastoma (GBM) is considered to be due in part to the prevalent immunosuppression in the GBM tumor microenvironment. Immune suppression is mediated in part by resident microglia and bone-marrow-derived myeloid cells recruited during tumor progression. A paper by Blank et al published in a recent issue of The Journal of Pathology proposes a myeloid cell-mediated mechanism that could contribute to resistance to anti-VEGF/R in GBM patients. A granulocyte-rich GBM tumor microenvironment may push the associated microglia/macrophages to exhibit an activated and immune suppressive phenotype. The identification of pro-angiogenic factors produced by microglia/macrophages and granulocytes in such a tumor microenvironment may offer new targets for improving antiangiogenic therapy of GBM beyond VEGF. Further, consideration of parameters such as IDH status, corticosteroid dosage, tumor mutational burden, gender, vascular function, and pericyte coverage could exploit current immunotherapies to the fullest to reprogram the granulocyte-rich immunosuppressive GBM tumor microenvironment to an immunostimulatory one. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262382PMC
June 2021

Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma.

Gut 2021 Jan 11. Epub 2021 Jan 11.

Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objective: Intrahepatic cholangiocarcinoma (ICC)-a rare liver malignancy with limited therapeutic options-is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression.

Design: We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems.

Results: PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC.PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.
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http://dx.doi.org/10.1136/gutjnl-2020-322493DOI Listing
January 2021

In silico dynamics of COVID-19 phenotypes for optimizing clinical management.

Proc Natl Acad Sci U S A 2021 01;118(3)

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;

Understanding the underlying mechanisms of COVID-19 progression and the impact of various pharmaceutical interventions is crucial for the clinical management of the disease. We developed a comprehensive mathematical framework based on the known mechanisms of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, incorporating the renin-angiotensin system and ACE2, which the virus exploits for cellular entry, key elements of the innate and adaptive immune responses, the role of inflammatory cytokines, and the coagulation cascade for thrombus formation. The model predicts the evolution of viral load, immune cells, cytokines, thrombosis, and oxygen saturation based on patient baseline condition and the presence of comorbidities. Model predictions were validated with clinical data from healthy people and COVID-19 patients, and the results were used to gain insight into identified risk factors of disease progression including older age; comorbidities such as obesity, diabetes, and hypertension; and dysregulated immune response. We then simulated treatment with various drug classes to identify optimal therapeutic protocols. We found that the outcome of any treatment depends on the sustained response rate of activated CD8 T cells and sufficient control of the innate immune response. Furthermore, the best treatment-or combination of treatments-depends on the preinfection health status of the patient. Our mathematical framework provides important insight into SARS-CoV-2 pathogenesis and could be used as the basis for personalized, optimal management of COVID-19.
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http://dx.doi.org/10.1073/pnas.2021642118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826337PMC
January 2021

Vascular dysfunction promotes regional hypoxia after bevacizumab therapy in recurrent glioblastoma patients.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa157. Epub 2020 Nov 17.

Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Background: Hypoxia is a driver of treatment resistance in glioblastoma. Antiangiogenic agents may transiently normalize blood vessels and decrease hypoxia before excessive pruning of vessels increases hypoxia. The time window of normalization is dose and time dependent. We sought to determine how VEGF blockade with bevacizumab modulates tumor vasculature and the impact that those vascular changes have on hypoxia in recurrent glioblastoma patients.

Methods: We measured tumor volume, vascular permeability (Ktrans), perfusion parameters (cerebral blood flow/volume, vessel caliber, and mean transit time), and regions of hypoxia in patients with recurrent glioblastoma before and after treatment with bevacizumab alone or with lomustine using [F]FMISO PET-MRI. We also examined serial changes in plasma biomarkers of angiogenesis and inflammation.

Results: Eleven patients were studied. The magnitude of global tumor hypoxia was variable across these 11 patients prior to treatment and it did not significantly change after bevacizumab. The hypoxic regions had an inefficient vasculature characterized by elevated cerebral blood flow/volume and increased vessel caliber. In a subset of patients, there were tumor subregions with decreased mean transit times and a decrease in hypoxia, suggesting heterogeneous improvement in vascular efficiency. Bevacizumab significantly changed known pharmacodynamic biomarkers such as plasma VEGF and PlGF.

Conclusions: The vascular signature in hypoxic tumor regions indicates a disorganized vasculature which, in most tumors, does not significantly change after bevacizumab treatment. While some tumor regions showed improved vascular efficiency following treatment, bevacizumab did not globally alter hypoxia or normalize tumor vasculature in glioblastoma.
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http://dx.doi.org/10.1093/noajnl/vdaa157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764510PMC
November 2020

A metastasis map of human cancer cell lines.

Nature 2020 12 9;588(7837):331-336. Epub 2020 Dec 9.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Most deaths from cancer are explained by metastasis, and yet large-scale metastasis research has been impractical owing to the complexity of in vivo models. Here we introduce an in vivo barcoding strategy that is capable of determining the metastatic potential of human cancer cell lines in mouse xenografts at scale. We validated the robustness, scalability and reproducibility of the method and applied it to 500 cell lines spanning 21 types of solid tumour. We created a first-generation metastasis map (MetMap) that reveals organ-specific patterns of metastasis, enabling these patterns to be associated with clinical and genomic features. We demonstrate the utility of MetMap by investigating the molecular basis of breast cancers capable of metastasizing to the brain-a principal cause of death in patients with this type of cancer. Breast cancers capable of metastasizing to the brain showed evidence of altered lipid metabolism. Perturbation of lipid metabolism in these cells curbed brain metastasis development, suggesting a therapeutic strategy to combat the disease and demonstrating the utility of MetMap as a resource to support metastasis research.
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http://dx.doi.org/10.1038/s41586-020-2969-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439149PMC
December 2020

Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma.

J Immunother Cancer 2020 11;8(2)

Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA

Background And Purpose: Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models.

Basic Procedures: We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20 mg/kg daily-combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer.

Main Findings: Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10-a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes-in murine HCC and in blood of patients with HCC. Using -deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy.

Principal Conclusions: Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.
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http://dx.doi.org/10.1136/jitc-2020-001435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689089PMC
November 2020

Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma.

Clin Cancer Res 2021 02 16;27(4):1048-1057. Epub 2020 Nov 16.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: VEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.

Patients And Methods: Eighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, = 50) or pembrolizumab monotherapy (cohort B, = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.

Results: Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3-41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7-14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7-25.4), median OS was 10.3 months (95% CI, 8.5-12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant , unmethylated , and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.

Conclusions: Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284901PMC
February 2021

Physical traits of cancer.

Science 2020 10;370(6516)

Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

The role of the physical microenvironment in tumor development, progression, metastasis, and treatment is gaining appreciation. The emerging multidisciplinary field of the physical sciences of cancer is now embraced by engineers, physicists, cell biologists, developmental biologists, tumor biologists, and oncologists attempting to understand how physical parameters and processes affect cancer progression and treatment. Discoveries in this field are starting to be translated into new therapeutic strategies for cancer. In this Review, we propose four physical traits of tumors that contribute to tumor progression and treatment resistance: (i) elevated solid stresses (compression and tension), (ii) elevated interstitial fluid pressure, (iii) altered material properties (for example, increased tissue stiffness, which historically has been used to detect cancer by palpation), and (iv) altered physical microarchitecture. After defining these physical traits, we discuss their causes, consequences, and how they complement the biological hallmarks of cancer.
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http://dx.doi.org/10.1126/science.aaz0868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274378PMC
October 2020

The Current Landscape of Immune Checkpoint Blockade in Hepatocellular Carcinoma: A Review.

JAMA Oncol 2021 Jan;7(1):113-123

Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts.

Importance: For more than a decade, sorafenib has been the only systemic treatment option for patients with advanced hepatocellular carcinoma (HCC). However, rapid progress over the past few years led to approval of other angiogenesis inhibitors and several immune checkpoint blockers (ICBs) that have been added to the treatment armamentarium for advanced HCC. Moreover, the recent success of a combination of bevacizumab with atezolizumab signals an important change in the front-line treatment of HCC.

Observations: This review summarizes rapidly emerging clinical data on the promise and challenges of implementing ICBs in HCC and discusses the unmet need of biomarkers to predict response or resistance to therapy. Two strategies to target immunosuppression in tumors are also discussed: one proven (vascular endothelial growth factor pathway inhibition) and one currently under investigation (transforming growth factor-β pathway inhibition). The rationale and preliminary evidence on how their inhibition may reprogram the immunosuppressive milieu and enhance the efficacy of ICBs in HCC are reviewed.

Conclusion And Relevance: The recent successes and failures of angiogenesis inhibitors and ICBs, alone and in combination, have provided important insights into how to implement this novel systemic therapy in HCC and led to new avenues to enhance immunotherapy efficacy in this disease.
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http://dx.doi.org/10.1001/jamaoncol.2020.3381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265820PMC
January 2021

NAD-mediated rescue of prenatal forebrain angiogenesis restores postnatal behavior.

Sci Adv 2020 Oct 9;6(41). Epub 2020 Oct 9.

Angiogenesis and Brain Development Laboratory, Huntington Medical Research Institutes (HMRI), 686 S Fair Oaks Avenue, Pasadena, CA 91105, USA.

Intrinsic defects within blood vessels from the earliest developmental time points can directly contribute to psychiatric disease origin. Here, we show that nicotinamide adenine dinucleotide (NAD), administered during a critical window of prenatal development, in a mouse model with dysfunctional endothelial γ-aminobutyric acid type A (GABA) receptors ( endothelial cell knockout mice), results in a synergistic repair of impaired angiogenesis and normalization of brain development, thus preventing the acquisition of abnormal behavioral symptoms. The prenatal NAD treatment stimulated extensive cellular and molecular changes in endothelial cells and restored blood vessel formation, GABAergic neuronal development, and forebrain morphology by recruiting an alternate pathway for cellular repair, via previously unknown transcriptional mechanisms and purinergic receptor signaling. Our findings illustrate a novel and powerful role for NAD in sculpting prenatal brain development that has profound implications for rescuing brain blood flow in a permanent and irreversible manner, with long-lasting consequences for mental health outcome.
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http://dx.doi.org/10.1126/sciadv.abb9766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546698PMC
October 2020

In silico dynamics of COVID-19 phenotypes for optimizing clinical management.

Res Sq 2020 Sep 3. Epub 2020 Sep 3.

Massachusetts General Hospital.

Understanding the underlying mechanisms of COVID-19 progression and the impact of various pharmaceutical interventions is crucial for the clinical management of the disease. We developed a comprehensive mathematical framework based on the known mechanisms of the SARS-CoV-2 virus infection, incorporating the renin-angiotensin system and ACE2, which the virus exploits for cellular entry, key elements of the innate and adaptive immune responses, the role of inflammatory cytokines and the coagulation cascade for thrombus formation. The model predicts the evolution of viral load, immune cells, cytokines, thrombosis, and oxygen saturation based on patient baseline condition and the presence of co-morbidities. Model predictions were validated with clinical data from healthy people and COVID-19 patients, and the results were used to gain insight into identified risk factors of disease progression including older age, co-morbidities such as obesity, diabetes, and hypertension, and dysregulated immune response . We then simulated treatment with various drug classes to identify optimal therapeutic protocols. We found that the outcome of any treatment depends on the sustained response rate of activated CD8 T cells and sufficient control of the innate immune response. Furthermore, the best treatment -or combination of treatments - depends on the pre-infection health status of the patient. Our mathematical framework provides important insight into SARS-CoV-2 pathogenesis and could be used as the basis for personalized, optimal management of COVID-19.
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http://dx.doi.org/10.21203/rs.3.rs-71086/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480033PMC
September 2020

A bilateral tumor model identifies transcriptional programs associated with patient response to immune checkpoint blockade.

Proc Natl Acad Sci U S A 2020 09 9;117(38):23684-23694. Epub 2020 Sep 9.

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;

Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8 T cells and fewer Gr1CD11b myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8 T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown in mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB.
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http://dx.doi.org/10.1073/pnas.2002806117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519254PMC
September 2020

Going Beyond VEGF Pathway Inhibition for Antiangiogenic Cancer Therapy: Is Inhibition of the PP2A/B55α Complex the Answer?

Circ Res 2020 08 27;127(6):724-726. Epub 2020 Aug 27.

the Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (D.G.D., R.K.J.).

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462096PMC
August 2020

In vivo compression and imaging in mouse brain to measure the effects of solid stress.

Nat Protoc 2020 08 17;15(8):2321-2340. Epub 2020 Jul 17.

Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

We recently developed an in vivo compression device that simulates the solid mechanical forces exerted by a growing tumor on the surrounding brain tissue and delineates the physical versus biological effects of a tumor. This device, to our knowledge the first of its kind, can recapitulate the compressive forces on the cerebellar cortex from primary (e.g., glioblastoma) and metastatic (e.g., breast cancer) tumors, as well as on the cerebellum from tumors such as medulloblastoma and ependymoma. We adapted standard transparent cranial windows normally used for intravital imaging studies in mice to include a turnable screw for controlled compression (acute or chronic) and decompression of the cerebral cortex. The device enables longitudinal imaging of the compressed brain tissue over several weeks or months as the screw is progressively extended against the brain tissue to recapitulate tumor growth-induced solid stress. The cranial window can be simply installed on the mouse skull according to previously established methods, and the screw mechanism can be readily manufactured in-house. The total time for construction and implantation of the in vivo compressive cranial window is <1 h (per mouse). This technique can also be used to study a variety of other diseases or disorders that present with abnormal solid masses in the brain, including cysts and benign growths.
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http://dx.doi.org/10.1038/s41596-020-0328-2DOI Listing
August 2020

Brain Metastasis Cell Lines Panel: A Public Resource of Organotropic Cell Lines.

Cancer Res 2020 10 8;80(20):4314-4323. Epub 2020 Jul 8.

Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, and Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Spread of cancer to the brain remains an unmet clinical need in spite of the increasing number of cases among patients with lung, breast cancer, and melanoma most notably. Although research on brain metastasis was considered a minor aspect in the past due to its untreatable nature and invariable lethality, nowadays, limited but encouraging examples have questioned this statement, making it more attractive for basic and clinical researchers. Evidences of its own biological identity (i.e., specific microenvironment) and particular therapeutic requirements (i.e., presence of blood-brain barrier, blood-tumor barrier, molecular differences with the primary tumor) are thought to be critical aspects that must be functionally exploited using preclinical models. We present the coordinated effort of 19 laboratories to compile comprehensive information related to brain metastasis experimental models. Each laboratory has provided details on the cancer cell lines they have generated or characterized as being capable of forming metastatic colonies in the brain, as well as principle methodologies of brain metastasis research. The Brain Metastasis Cell Lines Panel (BrMPanel) represents the first of its class and includes information about the cell line, how tropism to the brain was established, and the behavior of each model . These and other aspects described are intended to assist investigators in choosing the most suitable cell line for research on brain metastasis. The main goal of this effort is to facilitate research on this unmet clinical need, to improve models through a collaborative environment, and to promote the exchange of information on these valuable resources.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572582PMC
October 2020

Non-invasive monitoring of chronic liver disease via near-infrared and shortwave-infrared imaging of endogenous lipofuscin.

Nat Biomed Eng 2020 08 22;4(8):801-813. Epub 2020 Jun 22.

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.

Monitoring the progression of non-alcoholic fatty liver disease is hindered by a lack of suitable non-invasive imaging methods. Here, we show that the endogenous pigment lipofuscin displays strong near-infrared and shortwave-infrared fluorescence when excited at 808 nm, enabling label-free imaging of liver injury in mice and the discrimination of pathological processes from normal liver processes with high specificity and sensitivity. We also show that the near-infrared and shortwave-infrared fluorescence of lipofuscin can be used to monitor the progression and regression of liver necroinflammation and fibrosis in mouse models of non-alcoholic fatty liver disease and advanced fibrosis, as well as to detect non-alcoholic steatohepatitis and cirrhosis in biopsied samples of human liver tissue.
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http://dx.doi.org/10.1038/s41551-020-0569-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310386PMC
August 2020
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