Renu Dhanasekaran, Postdoctoral Faculty Sponsor
Renu Dhanasekaran, Postdoctoral Research Mentor
MYC Overexpression Drives Immune Evasion in Hepatocellular Carcinoma that is Reversible Through Restoration of Pro-Inflammatory Macrophages.
Cancers evade immune surveillance, which can be reversed through immune checkpoint therapy in a small subset of cases. Here we report that the MYC oncogene suppresses innate immune surveillance and drives resistance to immunotherapy. In 33 different human cancers, MYC genomic amplification and overexpression increased immune checkpoint expression, predicted non-responsiveness to immune checkpoint blockade, and was associated with both Th2-like immune profile and reduced CD8 T cell infiltration. MYC transcriptionally suppressed innate immunity and MHCI mediated antigen presentation, which in turn impeded T cell response. Combined, but not individual, blockade of PDL1 and CTLA4 could reverse MYC-driven immune suppression by leading to recruitment of pro-inflammatory antigen-presenting macrophages with increased CD40 and MHCII expression. Depletion of macrophages abrogated the anti-neoplastic effects of PDL1 and CTLA4 blockade in MYC-driven hepatocellular carcinoma (HCC). Hence, MYC is a predictor of immune checkpoint responsiveness and a key driver of immune evasion through the suppression of pro-inflammatory macrophages. The immune evasion by MYC in HCC can be overcome by combined PDL1 and CTLA4 blockade.
View details for DOI 10.1158/0008-5472.CAN-22-0232
View details for PubMedID 36525476
SPATIAL MULTI-OMIC IMMUNE PROFILING AND FUNCTIONAL CHARACTERIZATION OF HEPATOCELLULAR CARCINOMA (HCC) REVEAL MECHANISMS OF MINIMAL RESIDUAL DISEASE (MRD)
WILEY. 2022: S1278
View details for Web of Science ID 000870796604097
Toll-like receptor 4 selective inhibition in medullar microenvironment alters multiple myeloma cell growth
2022; 6 (2): 672-678
Bone marrow (BM) mesenchymal stromal cells (MSCs) are abnormal in multiple myeloma (MM) and play a critical role by promoting growth, survival, and drug resistance of MM cells. We observed higher Toll-like receptor 4 (TLR4) gene expression in MM MSCs than in MSCs from healthy donors. At the clinical level, we highlighted that TLR4 expression in MM MSCs evolves in parallel with the disease stage. Thus, we reasoned that the TLR4 axis is pivotal in MM by increasing the protumor activity of MSCs. Challenging primary MSCs with TLR4 agonists increased the expression of CD54 and interleukin-6 (IL-6), 2 factors directly implicated in MM MSC-MM cell crosstalk. Then, we evaluated the therapeutic efficacy of a TLR4 antagonist combined or not with conventional treatment in vitro with MSC-MM cell coculture and in vivo with the Vk*MYC mouse model. Selective inhibition of TLR4 specifically reduced the MM MSC ability to support the growth of MM cells in an IL-6-dependent manner and delayed the development of MM in the Vk*MYC mouse model by altering the early disease phase in vivo. For the first time, we demonstrate that specific targeting of the pathological BM microenvironment via TLR4 signaling could be an innovative approach to alter MM pathology development.
View details for DOI 10.1182/bloodadvances.2020003704
View details for Web of Science ID 000754639300011
View details for PubMedID 34714910
View details for PubMedCentralID PMC8791574
Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8(+) T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy
2020; 53 (4): 824-+
CD8+ T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8+ T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8+ T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226neg CD8+ T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8+ tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226-/- mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy.
View details for DOI 10.1016/j.immuni.2020.09.006
View details for Web of Science ID 000581062800014
View details for PubMedID 33053331
Imprinting of Mesenchymal Stromal Cell Transcriptome Persists even after Treatment in Patients with Multiple Myeloma
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
2020; 21 (11)
Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal expansion of malignant plasma cells (MM cells) in the bone-marrow (BM) compartment. BM mesenchymal stromal cells (MSC) from newly diagnosed MM patients were shown to be involved in MM pathogenesis and chemoresistance. The patients displayed a distinct transcriptome and were functionally different from healthy donors' (HD) MSC. Our aim was to determine whether MM-MSC also contributed to relapse.We obtained and characterized patients' MSC samples at diagnosis, two years after intensive treatment, without relapse and at relapse.Transcriptomic analysis revealed differences in gene expression between HD and MM-MSC, whatever the stage of the disease. An easier differentiation towards adipogenesis at the expense of osteoblatogeneis was observed, even in patients displaying a complete response to treatment. Although their transcriptome was similar, we found that MSC from relapsed patients had an increased immunosuppressive ability, compared to those from patients in remission.We demonstrated that imprinting of MSC transcriptome demonstrated at diagnosis of MM, persisted even after the apparent disappearance of MM cells induced by treatment, suggesting the maintenance of a local context favorable to relapse.
View details for DOI 10.3390/ijms21113854
View details for Web of Science ID 000543400300116
View details for PubMedID 32481768
View details for PubMedCentralID PMC7312921
Tumor cells educate mesenchymal stromal cells to release chemoprotective and immunomodulatory factors
JOURNAL OF MOLECULAR CELL BIOLOGY
2020; 12 (3): 202-215
Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. In this study, we characterize the mechanisms by which naïve mesenchymal stromal cells (MSCs) can acquire a CA-MSCs phenotype. Ovarian tumor cells trigger the transformation of MSCs to CA-MSCs by expressing pro-tumoral genes implicated in the chemoresistance of cancer cells, resulting in the secretion of high levels of CXC chemokine receptors 1 and 2 (CXCR1/2) ligands such as chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and interleukin 8 (IL-8). CXCR1/2 ligands can also inhibit the immune response against ovarian tumor cells. Indeed, through their released factors, CA-MSCs promote the differentiation of monocytes towards M2 macrophages, which favors tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 properties and acquire an anti-tumoral phenotype. Both ex vivo and in vivo, we used a CXCR1/2 inhibitor to sensitize ovarian tumor cells to carboplatin and circumvent the pro-tumoral effects of CA-MSCs. Since high concentrations of CXCR1/2 ligands in patients' blood are associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert carboplatin resistance.
View details for DOI 10.1093/jmcb/mjz090
View details for Web of Science ID 000529185400004
View details for PubMedID 31504643
View details for PubMedCentralID PMC7181721
Circulating CD14(high) CD16(low) intermediate blood monocytes as a biomarker of ascites immune status and ovarian cancer progression
JOURNAL FOR IMMUNOTHERAPY OF CANCER
2020; 8 (1)
Besides the interest of an early detection of ovarian cancer, there is an urgent need for new predictive and prognostic biomarkers of tumor development and cancer treatment. In healthy patients, circulating blood monocytes are typically subdivided into classical (85%), intermediate (5%) and non-classical (10%) populations. Although these circulating monocyte subsets have been suggested as biomarkers in several diseases, few studies have investigate their potential as a predictive signature for tumor immune status,tumor growth and treatment adaptation.In this study, we used a homogeneous cohort of 28 chemotherapy-naïve patients with ovarian cancer to evaluate monocyte subsets as biomarkers of the ascites immunological status. We evaluated the correlations between circulating monocyte subsets and immune cells and tumor burden in peritoneal ascites. Moreover, to validate the use of circulating monocyte subsets tofollow tumor progression and treatment response, we characterized blood monocytes from ovarian cancer patients included in a phase 1 clinical trial at baseline and following murlentamab treatment.We demonstrate here a robust expansion of the intermediate blood monocytes (IBMs) in ovarian cancer patients. We establish a significant positive correlation between IBM percentage and tumor-associate macrophages with a CCR2high/CD163high/CD206high/CD86lowprofile. Moreover, IBM expansion is associated with a decreased effector/regulatory T-cell ratio in ascites and with the presence of soluble immunosuppressive mediators. We also establish that IBM proportion positively correlates with the peritoneum tumor burden. Finally, the study of IBMs in patients with ovarian cancer under immunotherapy during the phase clinical trial supports IBMs to follow the evolution of tumor development and the treatment adaptation.This study, which links IBM level with immunosuppression and tumor burden in peritoneum, identifies IBMs as apotential predictive signature of ascites immune status and as a biomarker ofovarian cancer development and treatment response.EudraCT: 2015-004252-22 NCT02978755.
View details for DOI 10.1136/jitc-2019-000472
View details for Web of Science ID 000544562600016
View details for PubMedID 32503947
View details for PubMedCentralID PMC7279676