1) Immune checkpoint inhibition and anti-tumor immunity. Since my recruitment from UNC to UTHSC, I have established a robust collaboration with Dr. Joe Pierre in Pediatrics where my expertise in obesity and cancer have complemented well his expertise in obesity and the microbiome. The basis of our R01 (2020-2025) is focused on microbially-derived metabolites in breast cancer, using bariatric surgical weight loss approaches, immune checkpoint inhibitors, and pharmaceuticals to reprogram the immune microenvironment to improve anti-tumor immunity (Imm Rev ’20, Imm Rev ’20, Front Cell Dev Bio ’20, Cancer Metastasis Rev ’22). Our other R01 focuses on genetic variants impacting immunotherapy. I have also contributed to projects in the Pierre lab on the role of fungi in obesity and insulin resistance (manuscripts in prep). We demonstrated that the microbiome of both breast and tumor are associated with race for the first time, as well as tumor stage or tumor subtype (Sci Reports ’19). Makowski Lab has demonstrated expertise in myeloid reprogramming by obesity (Sipe Elife), iron sequestration (Accepted, in press), and PKC agonism (Mary Kay Foundation award, Cancer Letters, and in prep) which highlights our expertise in immunotherapy.
- Sipe LM#, Chaib M#, Korba EB#, Jo H, Lovely MC#, Counts BR, Tanveer U, Jolt JR, Clements JC#, John NA#, Daria D, Marion TN, Bohm MS#, Sekhri R, Pingili AK, Teng B, Carson JA, Hayes DN, Davis MJ, Cook KL, Pierre JF, Makowski Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery. Elife. 2022 Jul 1;11:e79143. PMID: 35775614.
- Chaib M#, Sipe LM#, Yarbro JR, Bohm MS#, Counts BR, Tanveer U, Pingili AK, Daria D, Marion TN, Carson JA, Thomas PG, Makowski L. PKC Agonism Restricts Innate Immune Suppression, Promotes Antigen Cross-Presentation and Synergizes with Agonistic CD40 Antibody Therapy to Activate CD8+ T cells in Breast Cancer. Cancer Lett. 2022 Jan 21;531:98-108. PMID: 35074498.
- #Sipe LM*, #Chaib M*, Pingili AK, Pierre JF, Makowski L. Microbiome, Bile Acids, and Obesity: How Microbially Modified Metabolites Shape Anti-Tumor Immunity. Immunological Reviews. 2020 May;295(1):220-239. PMID32320071. *co-first
- Pingili AK*, Chaib M#*, Sipe LM#, Miller EJ#, Teng B, Sharma R#, Yarbro JR, Asemota S, Al Abdallah Q, Mims TS, Marion TN, Daria D, Sekhri R, Hamilton AM, Troester MA, Jo H, Choi HY, Hayes DN, Cook KL, Narayanan R, Pierre JF*, Makowski L*. Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer. Cell Reports. 35;12, 109285, 2021. PMID34161764
2) Demonstrated that immunometabolic reprogramming directs macrophage biology in inflammation, efferocytosis, phagocytosis, atherosclerosis, and systemic glucose intolerance. i) We reported that fatty acid transport protein (FATP1) regulates macrophage lipid metabolism and glucose tolerance in obesity (Molecular Metabolism ‘16). ii) We showed that glucose transporter 1 (GLUT1) expression drove glucose uptake, reactive oxygen species generation, and inflammation in macrophages (J Biol Chem ‘14). iii) Using a novel model created in our lab, we discovered defects in macrophage infiltration and pro-inflammatory activation in the absence of macrophage GLUT1 when mice were made obese (Journal of Immunology, ’19). iv) With American Heart Association funding, we showed that 1) GLUT1 is central for macrophage efferocytosis and may contribute to necrosis in an atherosclerotic lesion (JI ‘18: Nature ‘18); and 2) FATP1 regulates atherosclerotic lesions (Atherosclerosis ‘17).
- Freemerman AJ*, Zhao L*^, Pingili AK, Teng B, Cozzo AJ^, Fuller AM^, Johnson AR^, Milner JJ^, Lim MF^, Galanko JA, Beck MA, Bear JE, Rotty JD, Lee DP, Bezavada L, Smallwood HS, Puchowicz MA, Liu J, Locasale JW, Bennett BJ, Abel ED, Rathmell JC, Makowski L. Myeloid Slc2a1-Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1. Journal of Immunology. 2019. PMC6360258.
- Morioka S, Perry JSA, Raymond MH, Medina CB, Zhu Y, #Zhao L, Serbulea V, Onengut-Gumuscu S, Leitinger N, Kucenas S, Rathmell JC, Makowski L, and Ravichandran KS. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature, PMC6331005.
- #Johnson AR*, #Qin YY*, #Cozzo A, Freemerman AJ, #Huang MJ, #Zhao L, #Sampey BP, #Milner JJ, Beck MA, Edin ML, Zeldin D, Galanko JA, Lee DP, Fueger PT, Damania B, Bivins B, Stahl A, Wu Y, Mohlke K, Makowski L. Macrophage Fatty Acid Transporter 1 (FATP1) Drives Alternative Macrophage Polarization and Limits Obesity-Induced Inflammation. *denotes co-first authorship. Molecular Metabolism, PMC4921943.
- Freemerman AJ, #Johnson AR, #Sacks GN, #Milner JJ, Kirk EL, Troester MA, Macintyre AN, Goraksha-Hicks P, Rathmell JC, Makowski L. Metabolic reprogramming of macrophages: Glucose Transporter (GLUT1)-mediated glucose metabolism drives a pro- inflammatory phenotype. J Biol Chem. 2014. PMC3953299.
3) Established genetically engineered mouse model (GEMM) of obesity associated basal-like breast cancer and demonstrated role for HGF-cMet using translational multi-disciplinary approaches. i) Using a unique murine model that resembles human basal-like breast cancer (triple negative breast cancer, TNBC), we demonstrated that high fat diet-induced obesity drove aggressive tumors– e.g., early latency and accelerated progression with changes in growth factors and inflammatory cytokines regulated by adiposity (BCRT ’13). ii) We published the first evidence for obesity-induced HGF and activation of its receptor cMet in the etiology of basal-like breast cancer, which had not been previously identified in any cancer type as obesity sensitive. Based on these findings, I was awarded two grants including a highly competitive NCI Provocative Question R21 and Mary Kay Foundation grant to test the role of weight loss and pharmacologic inhibition of cMet in reducing BBC through reversal of obesity-associated factors. iii) Inhibition of cMet with a small molecule reduced tumor burden and angiogenesis (Springerplus ‘16). iv) We showed obesity-driven basal like TNBC could be reversed by weight loss -before tumor onset- in mice (Frontiers in Oncology ’14, CCI ’16). Obesity-driven activation of several kinases in pre-neoplastic lesions of the mammary gland were detected using proteomics/kinomics and specificity was determined by reversal of activation by weight loss (CCI ’16). In patients, v) We reported that a significant majority of patients with basal-like breast cancer had activation of the aforementioned HGF-cMet pathway. We provided in vitro evidence of the importance of stromal-epithelial interactions in cancer promotion (Breast Cancer Res ‘13). vi) In patients, elevated macrophages in the obese normal breast microenvironment were reported in subjects who have undergone reduction mammoplasty compared to non-obese (BRCT ‘11). vii) We showed that basal-like tumor cells activate macrophages to a greater extent than less aggressive luminal subtype breast cancer cells (Molecular Cancer Research ‘12). viii) More clinically aggressive breast cancer subtypes including basal-like displayed different metabolomic profiles than that of less aggressive tumors from patient samples using metabolomics. We further demonstrated that glucose metabolism, HGF, and GLUT1 were linked and integral in maintaining high glycolytic rates of human cancer cells in vitro (CCR ‘12). ix) Finally, we demonstrated that the breast tumor intrinsic subtype is reflected in cancer-adjacent “normal” tissue in patients (Cancer Epidemiol Biomarkers Prev ‘15).
- #Qin Y, #Sundaram S, #Essaid L, Miller SM, Darr DB, Galanko JA, Montgomery SA, Major B, Johnson GL, Troester MA, Makowski L. Weight loss reduces basal-like breast cancer through kinome reprogramming. 16:26 Cancer Cell International. PMC4818517.
- #Cozzo AJ*, #Sundaram S*, #Zattra O, #Qin Y, Freemerman AJ, #Essaid L, Darr DB, Montgomery SA, McNaughton KK, Ezzell JA, Galanko JA, Troester MA, Makowski L. cMET inhibitor crizotinib impairs angiogenesis and reduces tumor burden in the C3(1)-Tag model of basal-like breast cancer. Springer Plus Breast Cancer Collection Springerplus. 2016 PMC4799044 *co-first.
- #Sundaram S, #Le TL, #Essaid L, Freemerman AJ, #Huang MJ, Galanko JA, McNaughton KK, Bendt KM, Darr DB, Troester MA, Makowski L. Weight loss prevents obesity-associated basal-like breast cancer progression: Role of hepatocyte growth factor. Frontiers in Oncology PMC4085881.
4) Determined underlying mechanisms and metabolite biomarkers in GEMMs of obesity-associated ovarian cancer (OC) and endometrial cancer (EC) with clinical correlates. In patients and mice, briefly, we demonstrated that BMI and obesity is associated with OC or EC: Gyn Oncol ’16 PMID:27288544; Gyn Oncol ’14 PMID3904507; AJCR ’19 PMID31720081; Han Oncotarget ’17.
# Denotes students and postdoctoral fellows mentored by Makowski.