Although tumor-intrinsic fatty acid β-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell–derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.

High dose acetaminophen (AAP) has demonstrated promising results in early phase clinical trials for treatment of advanced malignancies. When administered concurrently with the CYP2E1 inhibitor fomepizole, AAP can be dose-escalated 100-fold relative to standard dosing without liver toxicity and without compromising anti-tumor activity. The current study used a 23-plex flow cytometry panel to study AAP-induced changes in the tumor immune microenvironment of syngeneic mouse breast tumors. Effects of AAP on macrophage function and antigen presentation, alone and in combination with PD-1 antibodies, were evaluated. Findings demonstrated that the vast majority of CD45+ cells in the triple negative breast cancer model are CD11b+ cells of the innate immune system. The CD11b+ cells in the tumor micro-environment of vehicle-treated mice were mostly comprised of GR1+ myeloid derived suppressor cells. On the other hand, the CD11b+ cells in the high dose AAP-treated mice were mostly of the activated macrophage phenotype (F4/80+CD80+MHCII+). In vitro studies were performed to better understand AAP effects on macrophage function. It was demonstrated that AAP enhances phagocytosis as well as antigen presentation by macrophages to antigen-reactive T-cells. These effects are amplified when PD-1 antibodies are combined with AAP in the in vitro antigen presentation assay. Furthermore, AAP has synergistic anti-tumor activity in vivo when combined with PD-1 antibody therapy, an effect that is macrophage dependent. The present study demonstrates profound AAP-induced changes in the tumor immune microenvironment including the differentiation of CD11b+ cells towards an activated "M1" macrophage phenotype.

Background/Objectives: Preclinical and clinical evidence supports a chaperone-based vaccination platform for cancer immunotherapy. The objective of this study is to interrogate the next generation of chaperone-based immune modulator, termed Flagrp170, which was constructed by fusing a defined NF-κB-activating microbial sequence with a large stress protein with a superior antigen-holding/presenting property in the setting of antigen-targeted cancer vaccination. Methods: Bone marrow-derived dendritic cells were treated with Flagrp170 protein or an unmodified parental chaperone molecule (i.e., Grp170), followed by an analysis of DC activation and DC-mediated T cell priming using both in vitro and in vivo models. Antitumor vaccine responses in mice receiving tumor antigens (e.g., gp100, Her2/neu) complexed with Flagrp170 or Grp170 were examined through multiple immune assays. The potential use of a Flagrp170-based chaperone vaccine to sensitize tumors to anti-PD-1 therapy was also evaluated. Results: Flagrp170 not only retains the intrinsic ability of the parent chaperone to facilitate antigen cross-presentation, but also acquires a unique capacity to stimulate DCs efficiently through the engagement of TLR5-NF-κB signaling. This chimeric chaperone shows superior activity compared to the unmodified parental molecule, resulting in enhanced DC activation and T cell priming. Vaccination with Flagrp170 complexed to tumor antigens induces a robust T cell response against primary tumors and metastases, a process critically dependent on CD8⁺ DCs. Additionally, the Flagrp170 chaperone vaccine can efficiently generate and expand tumor-reactive T cells. The consequent remodeling of the tumor microenvironment towards a Th1/Tc1 dominant immune phenotype significantly potentiates cancer responsiveness to anti-PD1 therapy. Conclusions: Given the safety and T cell stimulation profiles of the chaperone–antigen complex vaccine already established in our recent clinical trial, this new generation of chaperone cargo, capable of delivering both antigenic targets and pathogen-associated immunoactivating signals simultaneously, represents a promising strategy to potentially improve the low response rates in patients receiving immune checkpoint inhibitors.

Appendiceal adenocarcinoma is rare with variable presentations. Perforation of the appendix within prolapsed ostomy can have peritoneal spread for which intraperitoneal chemotherapy should be considered. Surveillance is essential for these patients.