Purpose: The addition of immune checkpoint blockade (ICB) to platinum/etoposide chemotherapy changed the standard of care for small cell lung cancer (SCLC) treatment. However, ICB addition only modestly improved clinical outcomes, likely reflecting the high prevalence of an immunologically “cold” tumor microenvironment in SCLC, despite high mutational burden. Nevertheless, some patients clearly benefit from ICB and recent reports have associated clinical responses to ICB in SCLC with A) decreased neuroendocrine characteristics and B) activation of NOTCH signaling. We previously showed that inhibition of the LSD1 demethylase activates NOTCH and suppresses neuroendocrine features of SCLC, leading us to investigate whether LSD1 inhibition would enhance the response to PD1 inhibition in SCLC. Experimental Design: We employed a syngeneic immunocompetent model of SCLC, derived from a genetically engineered mouse model harboring Rb1/Trp53 inactivation, to investigate combining the LSD1 inhibitor bomedemstat with anti-PD1 therapy. In vivo experiments were complemented by cell-based studies in murine and human models. Results: Bomedemstat potentiated responses to PD1 inhibition in a syngeneic model of SCLC, resulting in increased CD8+ T cell infiltration and strong tumor growth inhibition. Bomedemstat increased MHC class I expression in mouse SCLC tumor cells in vivo and augmented MHC-I induction by interferon-ɣ and increased killing by tumor specific T cells in cell culture. Conclusions: LSD1 inhibition increased MHC-I expression and enhanced responses to PD1 inhibition in vivo, supporting a new clinical trial to combine bomedemstat with standard of care PD1 axis inhibition in SCLC.

Despite significant recent advances in precision medicine, pancreatic ductal adenocarcinoma (PDAC) remains near-uniformly lethal. While immune-modulatory therapies hold promise to meaningfully improve outcomes for PDAC patients, development of such therapies requires an improved understanding of the immune evasion mechanisms that characterize the PDAC microenvironment. Here we show that cancer cell-intrinsic glutamic-oxaloacetic transaminase 2 (GOT2) shapes the immune microenvironment to suppress antitumor immunity. Mechanistically, we find that GOT2 functions beyond its established role in the malate-aspartate shuttle and promotes the transcriptional activity of nuclear receptor peroxisome proliferator-activated receptor delta (PPARd), facilitated by direct fatty acid binding. While GOT2 is dispensable for cancer cell proliferation in vivo, the GOT2-PPARd axis promotes spatial restriction of both CD4+ and CD8+ T cells from the tumor microenvironment. Our results demonstrate a non-canonical function for an established mitochondrial enzyme in transcriptional regulation of immune evasion, which may be exploitable to promote a productive antitumor immune response.

Supplementary Figure from A Cancer Cell–Intrinsic GOT2–PPARδ Axis Suppresses Antitumor Immunity

<div>Abstract<p>Despite significant recent advances in precision medicine, pancreatic ductal adenocarcinoma (PDAC) remains near uniformly lethal. Although immune-modulatory therapies hold promise to meaningfully improve outcomes for patients with PDAC, the development of such therapies requires an improved understanding of the immune evasion mechanisms that characterize the PDAC microenvironment. Here, we show that cancer cell–intrinsic glutamic-oxaloacetic transaminase 2 (GOT2) shapes the immune microenvironment to suppress antitumor immunity. Mechanistically, we find that GOT2 functions beyond its established role in the malate–aspartate shuttle and promotes the transcriptional activity of nuclear receptor peroxisome proliferator–activated receptor delta (PPARδ), facilitated by direct fatty acid binding. Although GOT2 is dispensable for cancer cell proliferation <i>in vivo</i>, the GOT2–PPARδ axis promotes spatial restriction of both CD4⁺ and CD8⁺ T cells from the tumor microenvironment. Our results demonstrate a noncanonical function for an established mitochondrial enzyme in transcriptional regulation of immune evasion, which may be exploitable to promote a productive antitumor immune response.</p>Significance:<p>Prior studies demonstrate the important moonlighting functions of metabolic enzymes in cancer. We find that the mitochondrial transaminase GOT2 binds directly to fatty acid ligands that regulate the nuclear receptor PPARδ, and this functional interaction critically regulates the immune microenvironment of pancreatic cancer to promote tumor progression.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-22-0845" target="_blank">See related commentary by Nwosu and di Magliano, p. 2237.</a>.</i></p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-10-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 2221</a></i></p></div>

Supplementary Figure from Inhibition of LSD1 with Bomedemstat Sensitizes Small Cell Lung Cancer to Immune Checkpoint Blockade and T-Cell Killing