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Rakesh Jain
Director, A.W. Cook Professor of Tumor Biology
Jain Lab

Jain Lab Research

For four decades, my research has focused on one challenge: improving the delivery and efficacy of anti-cancer therapeutics by normalizing the tumor microenvironment. Working on the hypothesis that the abnormal tumor microenvironment fuels tumor progression and treatment resistance, we developed an array of sophisticated imaging technologies and animal models as well as mathematical models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells and the extracellular matrix associated with tumors are abnormal, and these collaborate together to create a hostile tumor microenvironment characterized by hypoxia, low pH and high interstitial fluid pressure and solid stress. We next hypothesized that agents that induce “normalization” of the microenvironment can improve the treatment outcome. Indeed, we demonstrated that judicious use of antiangiogenic agents—originally designed to starve tumors—could transiently “normalize” tumor vasculature, alleviate hypoxia, increase delivery of drugs and anti-tumor immune cells, and improve the outcome of various therapies, including immunotherapy (Science 2005, 2019, 2020). In parallel, we provided compelling evidence for vascular normalization in cancer patients treated with antiangiogenic agents. In fact, vascular normalization and the resultant improvement in tumor perfusion and oxygenation associated with longer survival in patients (J Clinical Oncology 2013; Cancer Cell 2014; PNAS 2015). Our preclinical finding that vascular normalization can improve immunotherapy (PNAS 2012) was confirmed by others in randomized phase III trials on combining antiangiogenic therapy with immune-checkpoint inhibitors for lung, kidney, liver and endometrial cancers (New England J Medicine 2018, 2019, 2020), and led to the FDA approvals of six such combinations of antiangiogenic therapy and  immune-checkpoint inhibitors for these cancers (Science 2019).

 The normalization hypothesis also opened doors to treating various non-malignant diseases characterized by abnormal vasculature that afflict >500 million people worldwide, such as, tuberculosis (PNAS 2015) and neurofibromatosis-2 (NF2) (New England J. Medicine 2009). Based on our findings, bevacizumab was approved for NF2-schwannoma patients in UK in 2014. This hypothesis has also been validated by a number of laboratories worldwide and has changed the thinking about how antiangiogenic agents work alone and in combination with conventional and emerging therapeutics (Science 2005; New England J. Medicine 2009; Nature Rev Drug Discovery 2011; Physiological Rev 2011; Cancer Cell 2014; Nature Reviews Clinical Oncology 2018; Science 2019). 

 Finally, we discovered that anti-hypertensive drugs capable of “normalizing” the tumor matrix and stromal cells can reprogram the tumor microenvironment to an immunostimulatory milieu and improve the delivery and efficacy of cancer therapies, including immunotherapy (Nature Comm 2013; Cancer Discovery 2016; Science Translational Medicine 2017; PNAS 2019, 2020). A phase II trial (NCT01821729) led by my clinical collaborators provided compelling evidence in support of this emerging concept for improving the treatment outcome for patients with pancreatic ductal adenocarcinoma – a uniformly fatal disease (JAMA Oncology 2019). 

Rakesh K. Jain receives National Medal of Science at the White House! ->Click here for the webcast.


 Click here for Dr. Jain's CV

Lab News

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

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 O2 saturation were important for ICU admission models whereas eGFR <60 ml/min/1.73 m2, 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.

Article link

Tumor-promoting immune cells retrained to fight most aggressive type of brain cancer

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.

MGH press release

Journal article

Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade

Optimized exercise therapy induces vessel normalization, boosts antitumor effector cell infiltration and function, and delays tumor growth in a CXCR3 pathway/CD8+ T cell- dependent manner. This results in sensitization of refractory breast cancer to immune checkpoint blockade.

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Potential new treatment strategy for breast cancer cells that have spread to the brain

New research reveals that when breast cancer cells spread to the brain, they must boost production of fatty acids, the building blocks of fat, in order to survive there. The work, which is published in Nature Cancer and was led by investigators at Massachusetts General Hospital (MGH) and the Koch Institute of the Massachusetts Institute of Technology (MIT), points to a potential new treatment target for shrinking brain tumors that arise secondary to breast cancer.

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

Invited Commentary for Blank et al. Microglia/macrophages express alternative proangiogenic factors depending on granulocyte content in human glioblastoma. J Pathol 2021; 253: 160–173.


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Current Research

The spread of cancer cells from primary tumors to regional lymph nodes is often associated with reduced survival. One prevailing model to explain this association posits that fatal, distant metastases are seeded by lymph node metastases. This view provides a mechanistic basis for the TNM staging system and is the rationale for surgical resection of tumor-draining lymph nodes. Here we examine the evolutionary relationship between primary tumor, lymph node, and distant metastases in human colorectal cancer. Studying 213 archival biopsy samples from 17 patients, we used somatic variants in hypermutable DNA regions to reconstruct high-confidence phylogenetic trees. We found that in 65% of cases, lymphatic and distant metastases arose from independent subclones in the primary tumor, whereas in 35% of cases they shared common subclonal origin. Therefore, two different lineage relationships between lymphatic and distant metastases exist in colorectal cancer.

Science. 2017;357(6346):55-60 - PMID: 28684519 - PMCID: PMC5536201 - DOI: 10.1126/science.aai8515

Angiotensin system inhibitors (ASIs) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients.<br /><br />Experimental Design: We performed an analysis of the records of ASI users and non-user patients with PDAC seen at Massachusetts General Hospital between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA-Seq of resected primary lesions. <br /><br />Results: 794 consecutive patients were included. In 299 resected patients, ASI-users experienced longer overall survival (OS) in both univariate (median OS: 36.3 vs. 19.3 months, p=0.011) and adjusted multivariate (HR, 0.505; 95%CI, 0.339 – 0.750; p=0.001) analyses. Propensity score adjusted analysis also showed a longer median OS for chronic ASI-users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI-users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g. WNT and Notch signaling) and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature which is predictive of survival in independent validation cohorts.<br /><br />Conclusions: In patients with non-metastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASI reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC.

Clin Cancer Res. 2017;23(19):5959-5969 - PMID: 28600474 - PMCID: PMC5856249 - DOI: 10.1158/1078-0432.CCR-17-0256

It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacological inhibition of angiotensin-II type-1 receptor (AT1) reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSCs) in obesity is induced by tumor-associated neutrophils (TANs) recruited by adipocyte-secreted IL-1ß. PSCs further secrete IL-1ß, and inactivation of PSCs reduces IL-1ß expression and TAN recruitment. Furthermore, depletion of TANs, IL-1ß inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In pancreatic cancer patients, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that crosstalk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity.

Cancer Discov. 2016;6(8):852-69 - PMID: 27246539 - PMCID: PMC4972679 - DOI: 10.1158/2159-8290.CD-15-1177

Polarization of tumor-associated macrophages: a novel strategy for vascular normalization and antitumor immunity.

TAMs with M2-like phenotype lead to abnormal tumor vasculature by producing angiogenic factors, such as PlGF, and M2-cytokines, such as IL10 and CCL22. In addition, M2-cytokines suppress immune cell functions. Elevated levels of HRG polarize TAMs away from an M2-like phenotype to normalize tumor vessels and activate anti-tumor immunity. By fortifying tumor vessels, vascular normalization may decrease shedding of metastatic cells into circulation resulting in decreased metastasis. Normalized vessels may also facilitate delivery of drugs and immune cells. Reduction in hypoxia – known to increase resistance to radiation and a number of therapeutics – also sensitizes tumors to various therapies and decreases selection pressure for more malignant clone, and promotes M1-like TAM phenotype. All these effects of HRG treatment may result in decreased tumor growth and metastasis and increased efficacy of various therapies. PlGF deletion in macrophages can phenocopy many effects of HRG treatment. (Schematics of abnormal and normalized tumor vasculature reproduced from Jain, Nat Med 7:987, 2001).

Cancer Cell. 2011;19(1):1-2 - PMID: 21251607 - PMCID: PMC3037265 - DOI: 10.1016/j.ccr.2011.01.005

Rapid blood perfusion is critical for postimplantation survival of thick, prevascularized bioartificial tissues. Yet the mechanism by which implanted vascular networks inosculate, or anastomose, with the host vasculature has been unknown, making it difficult to develop optimized strategies for facilitating perfusion. Here we show that implanted vascular networks anastomose with host vessels through a previously unidentified process of &quot;wrapping and tapping&quot; between the engrafted endothelial cells (ECs) and the host vasculature. At the host-implant interface, implanted ECs first wrap around nearby host vessels and then cause basement membrane and pericyte reorganization and localized displacement of the underlying host endothelium. In this way, the implanted ECs replace segments of host vessels to divert blood flow to the developing implanted vascular network. The process is facilitated by high levels of matrix metalloproteinase-14 and matrix metalloproteinase-9 expressed by the wrapping ECs. These findings open the door to new strategies for improving perfusion of tissue grafts and may have implications for other physiologic and pathologic processes involving postnatal vasculogenesis.

Blood. 2011;118(17):4740-9 - PMID: 21835951 - PMCID: PMC3208287 - DOI: 10.1182/blood-2011-02-338426

Jain Lab Careers

Postdoctoral fellowship on reprogramming pancreatic ductal adenocarcinoma microenvironment to improve immunotherapy

Investigator: Jain, Rakesh
Date Posted: 2021-09-15
Description
The Steele Laboratories at Massachusetts General Hospital and Harvard Medical School are currently seeking postdoctoral fellow applicants to define the molecular and cellular mechanism underlying the reprogramming of tumor microenvironment to improve immunotherapy. Applicants with a strong training background, experience and publication track record in the following areas are highly encouraged to apply – molecular and cell biology, flow cytometry and FACS, omics (genomics, transcriptomics proteomics and metabolomics), immunohistochemistry and imaging, and/or murine models of cancer.
Responsibilities
Individuals must have a Ph.D. M.D., and/or equivalent degree, appropriate research experience, strong organizational, interpersonal, communication, and computer skills and be prepared to work in a dynamic team environment. To begin the application process, please e-mail a current CV and statement of purpose to jobs@steele.mgh.harvard.edu.
Requirements
The Steele Laboratories at Massachusetts General Hospital and Harvard Medical School are currently seeking postdoctoral fellow applicants to define the molecular and cellular mechanism underlying the reprogramming of tumor microenvironment to improve immunotherapy. Applicants with a strong training background, experience and publication track record in the following areas are highly encouraged to apply – molecular and cell biology, flow cytometry and FACS, omics (genomics, transcriptomics proteomics and metabolomics), immunohistochemistry and imaging, and/or murine models of cancer.

Postdoctoral Fellow

Investigator: Jain, Rakesh
Date Posted: 2017-01-13
Description
The Steele Laboratory is currently seeking a postdoctoral applicant with expertise in breast cancer cell signaling and microenvironment. The position requires a highly motivated and independent researcher to carry out a project aimed at exploring brain-dependent signaling mechanisms to overcome resistance to targeted therapy andto restore anti-tumor immunity. Please see our recent papers for more information about our focus and experimental setup: 1) Askoxylakis et. al., Preclinical Efficacy of Ado-trastuzumab Emtansine in the Brain Microenvironment, JNCI 2015 2) Kodack et. al., Emerging strategies for treating brain metastases from breast cancer, Cancer Cell 2015. Experience in the following technical areas is preferred: molecular and cell biology, biochemistry, flow cytometry and FACS, immunohistochemistry and imaging, and murine models of cancer.
Requirements
Individuals must have a Ph.D. and/or M.D., appropriate research experience, strong organizational, interpersonal, communication, and computer skills and be prepared to work in a dynamic team environment. Applicants with a strong training background and publication track record in brain tumors are highly encouraged to apply. Experience in the following technical areas is preferred: immunohistochemistry, imaging and murine models of cancer. To begin the application process, please e-mail a current CV and statement of purpose to jobs@steele.mgh.harvard.edu

Postdoctoral Fellowship in Tuberculosis Granuloma Microenvironment

Investigator: Jain, Rakesh
Date Posted: 2017-01-13
Description
The Steele Laboratories are currently seeking postdoctoral applicants with expertise in tuberculosis research with extensive experience in immunohistochemistry and tuberculosis pathology. Experience with image analysis is highly preferred. The postdoctoral fellow will participate in an exciting multidisciplinary project aimed at studying the vasculature and matrix of tuberculosis granulomas. The project is funded by the Bill and Melinda Gates Foundation to Prof. Rakesh Jain, with leading tuberculosis collaborators from the NIH and Rutgers University.
Requirements
Individuals must have a Ph.D. and/or M.D., appropriate research experience, strong organizational, interpersonal, communication, and computer skills and be prepared to work in a dynamic team environment. US citizens and permanent US residents are encouraged to apply. To begin the application process, please e-mail a current CV and statement of purpose tojobs@steele.mgh.harvard.edu

Postdoctoral Fellowship in Glioblastoma Microenvironment and Anti-Tumor Immunity

Investigator: Jain, Rakesh
Date Posted: 2017-01-13
Description
The Steele Laboratories are currently seeking postdoctoral applicants with expertise in glioblastoma immunity and microenvironment to explore alternatives to current anti-VEGF treatment and modulation of the associated tumor immune component. Applicants with a strong training background and publication track record in immunology are highly encouraged to apply. Experience in the following technical areas is preferred: molecular and cell biology, flow cytometry and FACS, immunohistochemistry and imaging, and murine models of cancer.
Requirements
Individuals must have a Ph.D. and/or M.D., appropriate research experience, strong organizational, interpersonal, communication, and computer skills and be prepared to work in a dynamic team environment. US citizens and permanent US residents are encouraged to apply. To begin the application process, please e-mail a current CV and statement of purpose to jobs@steele.mgh.harvard.edu

Postdoctoral Fellow in Brain Tumors and Intravital Microscopy

Investigator: Jain, Rakesh
Date Posted: 2017-01-13
Description
The Steele Laboratory is currently seeking a postdoctoral applicant with training and research experience in tumor biology to carry out exciting multidisciplinary projects aimed at understanding tumor microenvironment in brain tumors. Expertise in animal studies and intravital imaging are necessary for the study.
Requirements
Individuals must have a Ph.D. and/or M.D., appropriate research experience, strong organizational, interpersonal, communication, and computer skills and be prepared to work in a dynamic team environment. Applicants with a strong training background and publication track record in brain tumors are highly encouraged to apply. Experience in the following technical areas is preferred: immunohistochemistry, imaging and murine models of cancer. To begin the application process, please e-mail a current CV and statement of purpose to jobs@steele.mgh.harvard.edu

Postdoctoral Fellow in pediatric brain tumors

Investigator: Jain, Rakesh
Date Posted: 2017-01-13
Description
The Steele Laboratory is currently seeking a postdoctoral applicant with training and research experience in tumor biology to carry out exciting multidisciplinary projects aimed at understanding the tumor micro-environment in pediatric brain tumors. Expertise in molecular biology, immunology, animal study and intra-vital imaging are necessary for the study.
Responsibilities
Individuals must have a Ph.D. and/or M.D., appropriate research experience, strong organizational, interpersonal, communication, and computer skills and be prepared to work in a dynamic team environment. Experience in the following technical areas is preferred: molecular and cell biology, flow cytometry and FACS, immunohistochemistry, imaging and murine models of cancer. To begin the application process, please e-mail a current CV and statement of purpose to jobs@steele.mgh.harvard.edu

Selected Publications (from total of 754)

Munn LL, Jain RK
Vascular regulation of antitumor immunity.
Science. 2019;365(6453):544-545 - PMID: 31395771 - PMCID: PMC7321824 - DOI: 10.1126/science.aaw7875
Mitchell MJ, Jain RK, Langer R
Engineering and physical sciences in oncology: challenges and opportunities.
Nat Rev Cancer. 2017;17(11):659-675 - PMID: 29026204 - PMCID: PMC5683724 - DOI: 10.1038/nrc.2017.83
Pinter M, Jain RK
Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy.
Sci Transl Med. 2017;9(410):ePub - PMID: 28978752 - PMCID: PMC5928511 - DOI: 10.1126/scitranslmed.aan5616
Kodack DP, Askoxylakis V, Ferraro GB, Sheng Q, Badeaux M, Goel S, Qi X, Shankaraiah R, Cao ZA, Ramjiawan RR, Bezwada D, Patel B, Song Y, Costa C, Naxerova K, Wong CSF, Kloepper J, Das R, Tam A, Tanboon J, Duda DG, Miller CR, Siegel MB, Anders CK, Sanders M, Estrada MV, Schlegel R, Arteaga CL, Brachtel E, Huang A, Fukumura D, Engelman JA, Jain RK
The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation.
Sci Transl Med. 2017;9(391):ePub - PMID: 28539475 - PMCID: PMC5917603 - DOI: 10.1126/scitranslmed.aal4682
Nia HT, Liu H, Seano G, Datta M, Jones D, Rahbari N, Incio J, Chauhan VP, Jung K, Martin JD, Askoxylakis V, Padera TP, Fukumura D, Boucher Y, Hornicek FJ, Grodzinsky AJ, Baish JW, Munn LL, Jain RK
Solid stress and elastic energy as measures of tumour mechanopathology.
Nat Biomed Eng. 2016;1:ePub - PMID: 28966873 - PMCID: PMC5621647 - DOI: 10.1038/s41551-016-0004
Jain RK
Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia.
Cancer Cell. 2014;26(5):605-622 - PMID: 25517747 - PMCID: PMC4269830 - DOI: 10.1016/j.ccell.2014.10.006
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