Rakesh Jain
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. 
Lab News
The Asian American Academy of Science and Engineering (AAASE) announced that Rakesh Jain has been elected to the inaugural class of Fellows. This distinguished group of scientists and engineers has been recognized for their exceptional contributions to their respective fields and their commitment to advancing the presence and influence of Asian Americans in science, technology, engineering, and mathematics.
- Approved drugs that were originally shown to normalize blood vessels surrounding tumors (to improve drug delivery to cancer cells) can enhance the delivery of anti-microbial medications to kill tuberculosis bacteria residing in the lungs
- These drugs (bevacizumab and losartan) alone and in combination with anti-microbial agents, promoted anti-bacterial host responses and improved health outcomes in lab models with tuberculosis
Congratulations on this achievement!
Research.com, a leading academic platform for researchers, has just released the 2023 Edition of its Ranking of Best Scientists in the field of Medicine.
Rakesh Jain was ranked #59 in the world ranking and #41 in United States. He has also been recognized with their Medicine Leader Award for 2023. Congratulations, Rakesh!
Current SARS-CoV-2 vaccines are effective at preventing COVID-19 or limiting disease severity in healthy individuals, but effectiveness is lower among patients with cancer or immunosuppression. A team led by Drs. Jain, Stylianopoulos and Munn predict vaccine effectiveness over time by building a mathematical framework to account for vaccination-induced immunity. A booster dose of both mRNA vaccines can induce a robust enhancement of both antibody levels and numbers of pertinent types of adaptive immune cells, which is predicted to provide sufficient protection for more than 1 y in healthy patients. However, the model suggests that for immunosuppressed people or patients with cancer receiving an immunosuppressive treatment, the booster effect may wane and should be given boosters on a more frequent basis.
Jain Lab Team
Former Team Members
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.
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.
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.
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).
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 "wrapping and tapping" 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.