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Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)- and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.

BackgroundCurrently, there is no standard biomarker that predict immunotherapy response in hepatocellular carcinoma (HCC). Here, we aim to investigate the role of tissue stiffness measured by magnetic resonance elastography (MRE) in predicting neoadjuvant immunotherapy response in patients with resectable HCC.MethodsThis was a study of 15 patients with HCC treated with immune checkpoint blockade (ICB) therapy, nivolumab ± ipilimumab, followed by surgical resection. HCC MRE assessment was performed at baseline and after 6 weeks of therapy. HCC stiffness (kPa) was measured on MRE elastograms (liver stiffness maps). Baseline stiffness and changes in stiffness were compared with treatment response to ICB. Treatment response was defined as a tumor with more than 60% necrosis which was the major pathological response. Analysis was performed using descriptive statistics, Fisher’s exact test, and Wilcoxon rank sum test; p-value ResultsFifteen patients were evaluable for MRE assessment. The median age was 67 years. Etiology of liver disease was NASH (n=4), HCV (n=3), HBV (n=2) and unknown (n=6). Three out of 15 patients (20%) achieved a major pathological response (MPR). Median baseline HCC stiffness and change in stiffness were 4.6 kPa and –0.2 kPa, respectively. Among the 4 patients with stiffness increase, 3 (75%) of them achieved MPR and 1 (25%) did not achieve MPR. Among the patients without stiffness increase, none of them achieved MPR. Fisher’s exact test indicates that increase in stiffness was associated with a higher chance to achieve MPR than patients without stiffness increase (p=0.0088). Median baseline HCC stiffness for responders and non-responders was 6.8 (5.4, 9) kPa and 3.9 (2.2, 9.7) kPa, respectively (p=0.09). The median change in HCC stiffness for responders and non-responders was 1 (1, 1.4) kPa and -0.4 (-2.2, 0.7) kPa, respectively (p=0.02).ConclusionsPatients who achieved MPR inclined to have a higher baseline stiffness than patients who did not achieve MPR. Regarding the changes in stiffness between the two arms, patients with MPR group had a greater increase than that in the non-MPR group. In conclusion, baseline and change in MRE stiffness may be a useful biomarkers in predicting response to ICB therapy in HCC.Ethics ApprovalThis was an Institutional Review Board approved study (MDACC 2017–0972). All patients provided written informed consent.

Background:AML is predominantly a disease of the elderly, yet outcomes remain dismal, particularly for relapsed/refractory (R/R) AML patients (pts). Gemtuzumab Ozogamicin (GO) is a monoclonal antibody targeting CD33–commonly expressed on AML blasts, and, critically, AML stem cells (LSC)–linked to the cytotoxin calicheamicin. GO resistance mechanisms include (i) decreased/aberrant blast CD33 expression, (ii) p-glycoprotein export of calicheamicin, and (iii) apoptosis resistance due to deficient activation of mitochondrial outer membrane permeabilization, a process highly dependent on BCL-2 expression. GO-induced apoptosis depends on the pro-apoptotic proteins Bax and Bak and is inhibited by overexpression of the anti-apoptotic proteins BCL-2 or BCL-XL. Venetoclax (VEN) is a BH3 mimetic, binding BCL-2, dislodging its binding to Bak/Bax, and thus facilitating apoptosis. LSC overexpress BCL-2, however VEN monotherapy is not effective in AML, as resistance develops rapidly. Hypothesis: VEN targeting of BCL-2 proteins that protect LSC from GO-induced apoptosis will synergistically increase GO efficacy. Correlative studies include pre-treatment AML blast BH3 profiling, CD33 expression (including sequencing for isoforms), and BCL-2, BCL-XL, and MCL-1 protein levels; MRD measurement at post-therapy time points using digital drop PCR technology; and quality of life assessments (EORTC QLQ-C30, FACT-Fatigue) Methods:This is a single arm, open-label, multi-center (BTCRC), dose-escalation phase Ib study of combination of VEN and GO in R/R AML pts (18-75y), using a 3+3 design. Major eligibility: ECOG 0-2, adequate organ function, CD33+ in ≥ 20% AML blasts, ≤ 3 lines of prior therapy, and no prior use of GO or VEN, previous VOD, BMT within 2 months, CNS disease, or history of HIV. Induction: 3-day VEN ramp-up to the target dose of 200 (cohort i), 400 (ii), or 600 (iii) mg daily x 28 d, with GO 3mg/m2 infused days 1, 4, and 7. If CR/CRi achieved, pts proceed to BMT if applicable, otherwise, if in CR/CRi (provided ANC > 1000, plts > 100K) or PR (regardless of counts), they are consolidated with VEN at the prescribed dose x 28d and GO 3mg/m2 on days 1 and 4 (Cycle 2). If BMT not applicable, and pt remaining in CR/CRi or PR (as above), then proceed to VEN alone as Maintenance in cycles 3+ until progression or toxicity. The primary endpoint is MTD of VEN with GO. Secondary endpoints include ORR, anti-leukemic activity, characterization of AEs, and estimates of RFS, EFS, and OS. Progress: This study is currently open to its second dosing cohort and has enrolled 5 pts to date. No dose-limiting toxicities have been encountered. However, the COVID-19 pandemic has had a negative impact on enrollment, which is expected to improve as vaccinations expand. ClinicalTrials.gov NCT04070768. Citation Format: Saad Arain, Pritesh Patel, Karen Sweiss, Brian Parkin, Heiko Konig, Gregory Calip, Betul Gok Yavuz, John Quigley. Phase Ib study of the safety and efficacy of Gemtuzumab Ozogamicin (GO) and Venetoclax in patients with relapsed or refractory CD33+ acute myeloid leukemia: Big Ten Cancer Research Consortium BTCRC-AML17-113 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT224.

Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumour microenvironment. CAFs have recently attracted attention for their function as a regulator of immune cell recruitment and function in addition to their tumour-promoting roles. In this study, we aimed to determine the role of CAFs on monocyte recruitment and macrophage polarization in breast cancer. CAFs, which were α-SMA expressing fibroblasts in contrast to normal fibroblasts (NFs), effectively recruited monocytes. Recruitment of monocytes by CAFs might be mediated by monocyte chemotactic protein-1 (MCP-1) as well as stromal cell-derived factor-1 (SDF-1) cytokines. CAFs differentiated the recruited monocytes into M2-like macrophages which are capable of exerting their immunosuppressive roles via the PD-1 axis. CAF-educated monocytes exhibited strong immune suppression unlike NF-educated monocytes and enhanced the motility/invasion of breast cancer cells in addition to increasing the expressions of epithelial–mesenchymal transition (EMT)-related genes and vimentin protein in cancer cells. CAF-educated M1 macrophages displayed increased expression of M2 markers and production of anti-inflammatory cytokine IL-10 in contrast to decreased production of pro-inflammatory cytokine IL-12 compared with control M1 macrophages; suggesting that CAFs were also able to induce the trans-differentiation of M1 macrophages to M2 macrophages. We then investigated the relationship between the infiltration of CAFs and tumour associated macrophages (TAMs) using tissue samples obtained from breast cancer patients. High grade of CAFs significantly correlated with the number of TAMs in human breast cancer tissue samples. It was also associated with higher Ki-67 proliferation index, and higher tumour volume. This result is in line with our finding of increased breast cancer cell proliferation due to the effects of CAF-educated monocytes in vitro. Our results concluded that CAFs play pivotal roles in sculpturing the tumour microenvironment in breast cancer, and therapeutic strategies to reverse the CAF-mediated immunosuppressive microenvironment should be taken into consideration.