One of the hallmarks of cancer is evading an immune response that should recognize emerging cancers as foreign and eliminate them. Immunotherapies are recent major breakthroughs in cancer treatment that reactivate the immune system to recognize and kill tumor cells. These novel treatments include immune checkpoint blockade where therapeutic antibodies remove a powerful break on the immune system to restore tumor killing, and cellular therapies where the patients’ own immune cells are engineered with superior tumor killing ability and then returned to the patient. Unfortunately, these new transformative treatments are only effective in a small subset of patients. If we could find the means to make immunotherapies more effective more broadly, it would transform cancer treatment and the lives of cancer patients.
One way to improve the anti-cancer immune response is by altering metabolism. Metabolic function and metabolite production can inhibit or promote activity of the immune system, but how they do so is poorly understood. It is the goal of the Ludwig Princeton Branch to understand how metabolism in tumor cells, the tumor microenvironment, and immune cells enables immune evasion. With that knowledge, we can identify the means to control metabolism through use of metabolic pathway inhibitors, metabolite supplementation, and dietary manipulation to restore the immune response to cancer and make immunotherapies more effective.
Related Publications
Khayati K, Bhatt V, Lan T, Alogaili F, Wang W, Lopez E, Hu ZS, Gokhale S, Cassidy L, Narita M, Xie P, White E, Guo JY. Cancer Research, 2022 Dec 2;CAN-22-1039. doi: 10.1158/0008-5472.CAN-22-1039. PMID: 36156071
Autophagy is a conserved catabolic process that maintains cellular homeostasis. Autophagy supports lung tumorigenesis and is a potential therapeutic target in lung cancer. A better understanding of the importance of tumor cell-autonomous versus systemic autophagy in lung cancer could facilitate clinical translation of autophagy inhibition. Here, we exploited inducible expression of Atg5 shRNA to temporally control Atg5 levels and generate reversible tumor-specific and systemic autophagy loss mouse models of KrasG12D/+;p53-/- (KP) non-small cell lung cancer (NSCLC). Transient suppression of systemic but not tumor Atg5 expression significantly reduced established KP lung tumor growth without damaging normal tissues. In vivo 13C isotope tracing and metabolic flux analyses demonstrated that systemic Atg5 knockdown specifically led to reduced glucose and lactate uptake. As a result, carbon flux from glucose and lactate to major metabolic pathways, including the tricarboxylic acid cycle, glycolysis, and serine biosynthesis, was significantly reduced in KP NSCLC following systemic autophagy loss. Furthermore, systemic Atg5 knockdown increased tumor T cell infiltration, leading to T cell-mediated tumor killing. Importantly, intermittent transient systemic Atg5 knockdown, which resembles what would occur during autophagy inhibition for cancer therapy, significantly prolonged lifespan of KP lung tumor-bearing mice, resulting in recovery of normal tissues but not tumors. Thus, systemic autophagy supports the growth of established lung tumors by promoting immune evasion and sustaining cancer cell metabolism for energy production and biosynthesis, and the inability of tumors to recover from loss of autophagy provides further proof of concept that inhibition of autophagy is a valid approach to cancer therapy.
Pérez-Núñez I, Rozalén C, Palomeque JÁ, Sangrador I, Dalmau M, Comerma L, Hernández-Prat A, Casadevall D, Menendez S, Liu DD, Shen M, Berenguer J, Ruiz IR, Peña R, Montañés JC, Albà MM, Bonnin S, Ponomarenko J, Gomis RR, Cejalvo JM, Servitja S, Marzese DM, Morey L, Voorwerk L, Arribas J, Bermejo B, Kok M, Pusztai L, Kang Y, Albanell J, Celià-Terrassa T. (2022) Nat Cancer, 3(3):355-370. PMID: 35301507
Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCORlow CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN.
Tang Y, Kang Y. (2022) Cell Metab, 34(4):506-507. PMID: 35385701
Immunotherapy has limited success in triple-negative breast cancer (TNBC). In this issue of Cell Metabolism, Wang et al. found that microbial metabolite TMAO boosts CD8+ T cell-mediated antitumor immunity by inducing pyroptosis in tumor cells, enhancing the efficacy of immunotherapy in TNBC (Wang et al., 2022).