A5059557053- Immune cells in cancer
- Cancer Immunotherapy and Biomarkers
- Nanoplatforms for cancer theranostics
- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- Chronic Myeloid Leukemia Treatments
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Immune Cell Function and Interaction
- RNA modifications and cancer
- Cancer-related molecular mechanisms research
- Chemokine receptors and signaling
- Tactile and Sensory Interactions
- Multiple Myeloma Research and Treatments
- Ferroptosis and cancer prognosis
- Interactive and Immersive Displays
- Adenosine and Purinergic Signaling
- Cancer, Stress, Anesthesia, and Immune Response
- T-cell and B-cell Immunology
- Metabolism, Diabetes, and Cancer
- Glioma Diagnosis and Treatment
- PARP inhibition in cancer therapy
- Melanoma and MAPK Pathways
- Genetic factors in colorectal cancer
- Cancer Mechanisms and Therapy
- Multisensory perception and integration
Cornell University
2020-2024
Weill Cornell Medicine
2022-2024
Swim Across America
2021-2024
Parker Institute for Cancer Immunotherapy
2024
Kettering University
2020-2022
Memorial Sloan Kettering Cancer Center
2020-2022
Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor efflux and enhanced glucose availability within the microenvironment (TME). LDH inhibitors (LDHi) reduce uptake growth preclinical models, but their impact tumor-infiltrating T cells not fully elucidated. have higher basal expression levels compared with infiltrating cells, creating therapeutic opportunity for...
The majority of JAK2 V617F -negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin ( CALR ), resulting a common carboxyl-terminal mutant fragment (CALR MUT representing an attractive source neoantigens for cancer vaccines. However, studies shown that -specific T cells are rare patients with MPN unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies from two independent cohorts. observed MHC-I alleles...
Abstract Over the past decade, immunotherapies have significantly improved clinical outcomes in cancer patients. The FDA approval of ICB for treatment represents a milestone, however, durable responses are observed only ∼20-40% immunosuppressive nature tumor microenvironment (TME) presents major challenge effective anti-tumor responses. Tumor cells highly metabolically active compared to other TME. Processes such as glycolysis and oxygen consumption (OXPHOS) lead hypoxia accumulation...
Abstract Immune checkpoint blockade (ICB) has yielded durable clinical responses which led to its FDA approval as a first-line therapy for melanoma and other malignancies. However, only ∼20-40% of patients show benefit when used monotherapies. This is mainly due inherent or acquired resistance these therapies within the tumor microenvironment (TME). There increasing evidence in pre-clinical studies that metabolism (e.g., glycolysis oxygen consumption (OXPHOS)) presents barrier anti-tumor...
Graphical information, such as illustrations, graphs, and diagrams, are an essential complement to text for conveying knowledge about the world. Although graphics can be communicated well via visual modality, this information touch has proven challenging. The lack of easily comprehensible tactile poses a problem blind. In paper, we advance hypothesis limited effectiveness graphics. contends that conventional rely upon embossings on two-dimensional surfaces do not allow deployment exploratory...
Abstract T cell immune checkpoint blockade (ICB) has shown remarkable promise in melanoma and other cancers. However, most patients do not show clinical benefit. This is because tumors can activate multiple checkpoints immunosuppressive pathways to evade anti-tumor responses. Inhibition of these suppressive mechanisms or repolarizing the tumor microenvironment (TME) become more accessible system may be necessary for maximal therapeutic efficacy immunotherapies. There increasing evidence that...
MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds and prevents release of RAF, reducing the relief negative feedback commonly observed with other MEKis. We CKI27 increased MHC expression in improved T cell-mediated killing. Yet, also decreased T-cell proliferation, activation, cytolytic activity by inhibiting pathway activated...
<div>Abstract<p>MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway–dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds MEK and prevents release of RAF, reducing the relief negative feedback commonly observed with other MEKis. We CKI27 increased MHC expression in improved T cell–mediated killing. Yet, also decreased T-cell proliferation, activation, cytolytic activity by...
<p>Supplemental Figure 11. The triple combination increases activation of CD8+ T cells and CD4+ Teffs while Tregs remain unaffected in LLC TDLN. (A) Schema tumor bearing mice treated with vehicle, CKI27, isotypes, GITR, and/or CTLA-4. All timepoints were harvested on day 21 (7 days post treatment). (B) Image TDLNs from mice. (C) Gating strategy for all vivo flow experiments. (D) Absolute number immune cell populations the TDLN; n=4-5. (E) Phenotypes n=9-10. Data are shown as mean±SEM....
<p>Supplementary Figure 2. MEK inhibition with CKI27 increases MHC and checkpoint ligand expression. Murine tumor cell lines were treated DMSO or for 72 hr either without IFNγ (5ng/mL) the last 24hr; n=3. FACS analysis of representative histograms MFI MHC-I (H2Kb/Kd H2Db/Dd), MHC-II, PD-L1, CD80 CD86 are shown.</p>
<p>Supplementary Figure 9. Intermittent CKI27 treatment and GITR engagement relieves suppressive effects of MEK inhibition on T cell proliferation, cytokine production, effector function. (A-C) Human PBMCs were labelled with CTV, sub-optimally stimulated 1:25 or 1:100 CD3/CD28 Dynabeads, treated DMSO, continuous (96hr), washout (24hr on, 72hr off), and/or GITR-L; n=2-3. (A) % proliferation CTVlow CD8+ CD4+ cells. (B) FACS analysis co-inhibitory, co-stimulatory, activation markers...
<p>Supplementary Figure 10. The triple combination reduces tumor growth, is T cell dependent, and protects from re-challenge in LLC CT26. (A-D) bearing mice were treated with vehicle, isotypes, GITR, CTLA-4, 5mg/kg 4on/3off CKI27, and/or CD8 for 4 weeks growth was monitored over time. (A) Average (volume, mm3) of immunocompetent mice. (B) immunodeficient (C) depleted (D) that re-challenged. (E-H) CT26 αCTLA-4, 2mg/kg αCD8 (E) (F) (G) (H) Two-way ANOVA test Bonferroni’s correction...
<p>Supplementary Figure 5. Intermittent CKI27 allows for immune cell recovery in the spleen, increases frequencies TDLN, and inhibits TILs similarly to continuous treatment. (A) Schema of LLC tumor bearing mice treated with vehicle, daily 2mg/kg CKI27, or intermittent 5mg/kg 4on/3off CKI27. Mice were a staggered schedule all timepoints harvested on day 23. (B-D) All fold changes calculated by normalizing DMSO. (B) Fold absolute number (cells/uL) spleen populations. (C) TDLN (D) weights...
<p>Supplementary Figure 1. MEK inhibition with CKI27 increases MHC and checkpoint ligand expression. (A-B) Murine tumor cell lines were treated DMSO or for 72 hr either without IFNγ (5ng/mL) the last 24hr; n=3. FACS analysis of (A) MHC-I (H2Kb/Kd H2Db/Dd) MHC-II (B) PD-L1, CD80 CD86 surface Median fluorescence intensity (MFI) values normalized to log transformed. Data are shown as mean±SEM.</p>
<p>Supplementary Figure 4. Intermittent CKI27 treatment partially relieves suppressive effects of MEK inhibition on T cell proliferation, cytokine production, and effector function. (A-C) Human PBMCs were labelled with CTV, sub-optimally stimulated 1:25 or 1:100 CD3/CD28 Dynabeads, treated DMSO, continuous (96hr) washout (24hr on, 72hr off); n=2-3. (A) Proliferation fold change CTVlow CD8+ CD4+ cells was calculated by normalizing to DMSO. (B) FACS analysis co-inhibitory,...
<p>Supplementary Figure 7. Intermittent CKI27 treatment and GITR co-stimulation relieves expression of co-stimulatory markers. Representative dot plot data for FACS analysis markers expressed by CD8+ T cells.</p>
<p>Supplementary Figure 6. Intermittent CKI27 treatment and GITR co-stimulation relieves expression of co-inhibitory markers. (A) Gating strategy for all T cell activation assays. (B) Representative dot plot data FACS analysis markers expressed by CD8+ cells.</p>
<p>Supplementary Figure 8. Intermittent CKI27 treatment and GITR co-stimulation relieves expression of activation markers. Representative dot plot data for FACS analysis markers expressed by CD8+ T cells.</p>
<p>Supplementary Figure 3. MEK inhibition with CKI27 increases HLA and checkpoint ligand expression. (A-B) Human tumor cell lines were treated DMSO or for 72hr either without IFNγ (10ng/mL) the last 24hr; n=3. FACS analysis of (A) HLA-ABC HLA-DR (B) PD-L1, CD80 CD86 surface MFI values are shown as mean±SEM.</p>
<p>Supplementary Figure 12. The triple combination increases activation of CD8+ T cells, CD4+ Teffs, and Tregs in CT26 TDLN. (A) Schema tumor bearing mice treated with vehicle, CKI27, isotypes, GITR, and/or CTLA-4. All timepoints were harvested on day 21 (7 days post treatment). (B) Absolute number immune cell populations the TDLN; n=4-5. (C) Phenotypes cells from Data are shown as mean±SEM. One-way ANOVA test Bonferroni’s correction for multiple comparisons was used all panels....
<p>Supplementary Figure 14. The triple combination increases activation of CD8+ T cells and CD4+ Teffs while destabilizing Tregs in CT26 tumor. (A) Schema tumor bearing mice treated with vehicle, CKI27, isotypes, GITR, and/or CTLA-4. All timepoints were harvested on day 21 (7 days post treatment). (B) Tumor weights, numbers cells/mg, CD8:Treg ratio TILs; n=4-5. (C) Phenotypes Data are shown as mean±SEM. One-way ANOVA test Bonferroni’s correction for multiple comparisons was used all...
<p>Supplementary Figure 15. The triple combination favorably alters the genetic profile of immune cells in TDLN. LLC tumor bearing mice were treated with vehicle, CKI27, isotypes, GITR, and/or CTLA-4. TLDNs harvested on day 21 (7 days post treatment). Live CD45+ FACS sorted and processed for sc-RNA sequencing. (A-B) Heatmap showing top genes expressed by each cluster (A) CD8+ (B) CD4+ T cells. (C) UMAPs treatment groups different clusters annotations. (D) from group specific activation...