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VIEWS IN THE SPOTLIGHT Epigenetic Modulation of the Tumor Immune Microenvironment to Potentiate Immune Checkpoint Blockade Therapy Johannes Menzel and Joshua C. Black Summary: Response rates to immune checkpoint blockade (ICB) in KRAS-mutant lung adenocarcinoma remain poor. In this issue of Cancer Discovery , Li and colleagues report an in vivo CRISPR screen of epigenetic regula- tors of the tumor immune microenvironment that uncovers Asf1a as a tumor-intrinsic suppressor of ICB through suppression of GM-CSF expression. See related article by Li et al., p. 270 (3). Lung adenocarcinoma is a leading cause of cancer-related would potentiate the effects of anti–PD-1 immunotherapy. death worldwide. Mutations in KRAS or EGFR are both Using this approach, the authors identifi ed that knockout major oncogenic drivers of lung cancer. Patients harboring (KO) of the histone H3-H4 chaperone Asf1a in the KP adeno- EGFR mutations can benefi t from EGFR tyrosine kinase carcinoma cells sensitizes the tumor to checkpoint blockade. inhibitors, but, despite the development of allele-specifi c Intriguingly, Asf1a knockout in the KP lung tumor cells KRAS G12C inhibitors, patients harboring KRAS mutations results in signifi cantly impaired tumor growth only when fail to benefi t from targeted inhibitors ( 1 ). The advance- treated with anti–PD-1. The combined Asf1a defi ciency and ment of immunotherapy is promising for treatment of anti–PD-1 treatment resulted in increased infl ammation, adenocarcinoma. Immune checkpoint blockade (ICB) thera- increased tumor-associated macrophages with M1-like polar- pies are now FDA-approved for the treatment of a broad ization, and increased T-cell infi ltration in the tumor. Single- range of tumor types, including adenocarcinoma. Novel cell sequencing confi rmed these results and also identifi ed therapies focused on the immune checkpoint inhibition of an increase in tumor-associated memory T cells. The authors PD-1 and CTLA4 have achieved clinical success in multiple confi rmed increased memory function by challenging mice cancers, including adenocarcinoma ( 2 ). However, only a sub- with a second xenograft. The mice originally exposed to the set of patients respond fully. Many aspects of ICB remain Asf1a KO anti–PD-1–treated tumors were able to suppress to be understood, and answering these questions should growth of the second round of tumors more effectively than help increase the number of patients who respond to ICB control mice. These results suggest that combining an ASF1A therapy. inhibitor and ICB could be effective in treating patients with In this issue of Cancer Discovery , Li and colleagues uncover adenocarcinoma. Furthermore, the induction of a memory- a novel means by which ICB can be made more effective in like function suggests that combined therapy could poten- KRAS-mutant lung cancer ( Fig. 1 ; ref. 3 ). Although ICB has tially be effective at suppressing metastasis and outgrowth proved effective for a subset of patients, response rates are at distant sites. only 10% to 15% in KRAS-mutant lung adenocarcinoma. Several other tumor types including non–small cell lung To overcome this problem, Li and colleagues reasoned that cancer and breast cancer have lower response rates to ICB, because epigenetic regulators in the tumor can control the and it remains unclear whether combined Asf1a defi ciency tumor microenvironment they may be ideal candidates for and ICB could be more universally applied ( 4, 5 ). The authors potential adjuvant therapy in combination with ICB. They began to address this issue by demonstrating that Asf1a KO thus conducted an in vivo CRISPR screen using a KRAS- in a mouse colon cancer model, the MC38 cell line, also mutant p53-null (KP) mouse lung adenocarcinoma cell line suppressed tumor growth in immunocompetent mice when in immunocompetent mice for epigenetic regulators that coupled with anti–PD-1 therapy. This suggests Asf1a may infl uence ICB in other cancers as well. Furthermore, analysis of data from The Cancer Genome Atlas shows a correlation between increased infl ammatory signaling in human patients Department of Pharmacology , University of Colorado Anschutz Medical with adenocarcinoma and lower expression of Asf1a , suggest- Campus, Aurora, Colorado. ing that the relationship may hold true in human patients Corresponding Author: Joshua C. Black , Department of Pharmacology, with adenocarcinoma and that it is worthwhile to examine University of Colorado School of Medicine Anschutz Medical Campus, Mail using expression of Asf1a as a potential biomarker to help Stop 8303, 12800 E. 19th Avenue, Room P18-6116, Aurora, CO 80045. identify patients with lung adenocarcinoma (or potentially Phone: 303-724-9991; E-mail: [email protected] other cancers) who would benefi t from ICB. Cancer Discov 2020;10:179–81 A question that remains from this study is how p53 status doi: 10.1158/2159-8290.CD-19-1349 may contribute to the effectiveness of combining ASF1A inhi- © 2020 American Association for Cancer Research. bition and ICB. In other tumor models, depletion of ASF1A FEBRUARY 2020 CANCER DISCOVERY | 179 Downloaded from cancerdiscovery.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. VIEWS Ineffective immune checkpoint blockade Improved immune checkpoint blockade Inflammatory Monocytes monocytes Memory T cells T cell Activated T cell M1-like PD-1 TCR PD-1 TCR macrophages Antitumor CD80 CD86 immunity Anti–PD-1 Anti–PD-1 PD-L1 PD-L1 MHC Asf1a Ast1aAstAsAstst1 GM-CSF GM-CSF Tumor cell Tumor cell Csf2/GM-CSF Csf2/GM-CSF Figure 1. Schematic representing core findings of Li and colleagues (3). The authors showed that deletion ofAsf1a sensitizes lung adenocarcinoma cancer cells to ICB using anti–PD-1 therapy. Deletion of Asf1a allows increased expression of the Csf2 gene, which encodes the cytokine GM-CSF. GM-CSF promotes recruitment and activation of T cells, polarization of macrophages to an M1-like state, and production of memory T cells. This inflamed tumor immune microenvironment results in enhanced tumor reduction and provides a rationale for future combination therapy with ASF1A inhibitors and ICB. TCR, T-cell receptor. has been shown to induce DNA damage and p53-dependent attempted to increase GM-CSF secretion from tumor cells by growth arrest and senescence of cancer cells (6). Here, Li and targeted inhibition of alternative checkpoints, by targeting colleagues use cell lines that are p53 null (KP) or p53 mutant pattern recognition receptors using oncolytic viruses, or by (MC38), and thus do not address how this combined therapy viral mimicry that expresses or activates proinflammatory would work in p53 wild-type cells. The authors comment that genes (7). Li and colleagues demonstrate that GM-CSF levels ASF1A depletion did not result in significant DNA damage are crucial for the antitumor growth effect of combined in contradiction to previously reported roles for ASF1A in anti–PD-1 and Asf1a KO in vivo, as treatment with GM-CSF nonhomologous end joining repair and the DNA damage neutralizing antibodies relieves the tumor growth suppres- checkpoint. Thus, it is possible that ASF1A inhibition and sion elicited by the combination treatment. Thus, ASF1A anti–PD-1 combination therapy may be effective only in cells regulates the tumor immune microenvironment, and sensi- with an inactivated or defective p53 pathway. It is also pos- tivity to ICB, through tumor-intrinsic transcriptional control sible that inhibiting ASF1A could have potential deleterious of inflammatory cytokines (Fig. 1). effects on noncancerous cells. However, this concern has been Traditionally, ASF1A functions as a histone chaperone for overcome with other cell-cycle inhibitors (such as hydroxyurea chromatin assembly in either the HIRA complex (replica- or vinblastine) by defining a safer therapeutic window where tion-independent histone deposition) or the CAF1 complex the toxicity is more significant in cancer cells. Future work (replication-dependent histone deposition). However, neither needs to address if the synergy between loss of ASF1A function HIRA nor CHAF1A/CHAF1B (the other components of the and anti–PD-1 treatment also exists for other methods of ICB CAF1 complex) synergized with anti–PD-1 therapy in the including anti–PD-L1 and anti-CTLA4. authors’ in vivo CRISPR screen. Furthermore, Asf1b, a closely To understand how Asf1a deletion sensitizes KP cells to related homolog that also functions with HIRA and CAF1 ICB, Li and colleagues conducted RNA sequencing of Asf1a in histone deposition, also did not emerge from the CRISPR KO KP cells with and without anti–PD-1 therapy. These screen. These data suggest that ASF1A may have a role in regu- experiments revealed increased expression of multiple inflam- lating gene expression independent of its function in histone matory pathways with consistent upregulation of GM-CSF. deposition as a member of the HIRA or CAF1 complex. Con- The gene encoding GM-CSF, Csf2, is directly bound by ASF1A sistent with this idea, Li and colleagues did not observe any in multiple cell types and is transcriptionally regulated by difference in chromatin accessibility at the GM-CSF/Csf2 gene ASF1A. GM-CSF is a secreted cytokine that directs hemat- in Asf1a KO cells by ATAC-seq. ASF1A has previously been opoietic stem cells to produce more monocytes and granulo- demonstrated to regulate gene expression in a manner likely cytes as well as promote immunity by directing recruitment independent of its chromatin assembly function.

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